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Innate Immune Cell Death in Neuroinflammation and Alzheimer’s Disease

Yetirajam Rajesh, Thirumala-Devi Kanneganti

Cells · 2022 · Review · CC BY

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder molecularly characterized by the formation of amyloid β (Aβ) plaques and type 2 microtubule-associated protein (Tau) abnormalities. Multiple studies have shown that many of the brain’s immunological cells, specifically microglia and astrocytes, are involved in AD pathogenesis. Cells of the innate immune system play an essential role in eliminating pathogens but also regulate brain homeostasis and AD. When activated, innate immune cells can cause programmed cell death through multiple pathways, including pyroptosis, apoptosis, necroptosis, and PANoptosis. The cell death often results in the release of proinflammatory cytokines that propagate the innate immune response and can eliminate Aβ plaques and aggregated Tau proteins. However, chronic neuroinflammation, which can result from cell death, has been linked to neurodegenerative diseases and can worsen AD. Therefore, the innate immune response must be tightly balanced to appropriately clear these AD-related structural abnormalities without inducing chronic neuroinflammation. In this review, we discuss neuroinflammation, innate immune responses, inflammatory cell death pathways, and cytokine secretion as they relate to AD. Therapeutic strategies targeting these innate immune cell death mechanisms will be critical to consider for future preventive or palliative treatments for AD.

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From PubMed Central, U.S. National Library of Medicine, as current on Oct 19, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

1Alzheimer’s disease (AD) is a debilitating disease affecting approximately 44 million people worldwide. The progression of this neurodegenerative disease varies between patients, and symptoms can take decades to develop. Dementia, characterized by progressive memory loss and cognitive impairment, is most often caused by AD. As dementia worsens, patients become unable to care for themselves and need constant monitoring and assistance before eventually succumbing to the effects of the disease. For these reasons, AD places an enormous burden on both individuals and society.

2AD is characterized by the presence of two structural brain abnormalities caused by the proteins amyloid β (Aβ) and type 2 microtubule-associated protein (Tau). The characteristic AD-inducing plaques, caused by Aβ deposition between nerve cells in the brain, can manifest several years before clinical symptoms unfold, and plaques play a major role in cognitive decline and neuronal cell death. Aβ is formed from amyloid precursor protein (APP) cleavage; APP is expressed in neurons and glial cells and is responsible for mediating cell-to-cell adhesion, neuronal signaling, and regulating neurotransmitter discharge. APP can be cleaved into peptides (37–49 amino acids in length) by several proteolytic secretases. Depending on which secretases cleave APP, the process is either termed amyloidogenic, which is associated with plaque formation and disease, or nonamyloidogenic. The nonamyloidogenic pathway is initiated by APP cleavage by α-secretase, followed by γ-secretase. The product is a non-toxic, soluble APPα fragment with essential neuroprotective functions. Alternatively, induction of the amyloidogenic pathway involves APP cleavage by β-secretase, which first generates a soluble APPβ peptide. This processing is followed with cleavage by γ-secretase, which cleaves the APP C-terminal fragment, generating neurotoxic Aβ peptides. Various lengths of Aβs form, but Aβ1-42 is the major component of plaque formation; Aβ1-42 has a highly hydrophobic C-terminus that initiates Aβ aggregation and oligomerizes into higher order insoluble structures that diffuse throughout the brain. These plaques interrupt cellular communication and can cause microglial activation and inflammation that ultimately can cause neuronal death and tissue damage in the brain.

3Along with Aβ aggregation, the dysregulation of the protein Tau also results in AD. Tau is expressed in neurons, astrocytes, and oligodendrocytes. Normally, Tau binds microtubules to stabilize them, impacting synaptic functions. However, abnormal post-translational modifications can hyper-phosphorylate Tau, causing dissociation from microtubules and intracellular aggregation via neurofibrillary tangles (NFTs). Tau hyperphosphorylation and NFTs are associated with AD pathogenesis. Additionally, Aβ deposition can drive Tau-mediated AD pathogenesis resulting in NFTs, cognitive impairment, and dementia.

4While Aβ plaques and NFTs in neurons are key features of AD, the disease pathogenesis is not limited to the neuronal compartment, and many of the brain’s immunological cells (astrocytes, microglia, and peripheral infiltrating immune cells) are also involved. The activation of astrocytes and microglial cells releases proinflammatory cytokines, including IL-1β, TNF-α, and IL-6; these cytokines can trigger Tau hyper-phosphorylation. Additionally, increased levels of proinflammatory cytokines have been found in the serum and brains of patients with AD compared with healthy patients, and this prolonged neuroinflammation can lead to the misfolding of Tau. These results collectively lay the groundwork for a strong connection between innate immunity and pathology in the central nervous system (CNS).

Innate Immune Signaling Pathways in the Central Nervous System

5Innate immune signaling pathways in microglial cells are activated in response to a myriad of stimuli such as infection, injury, and chronic disease. As a result of an activated immune response, programmed cell death (PCD) can occur and has a significant role in pathogenesis in the CNS, with specific roles in brain development, homeostasis, and clearance of infected/transformed cells. There are several forms of PCD with defined molecular signatures, ranging from the traditionally noninflammatory apoptosis pathway to highly proinflammatory forms of cell death such as pyroptosis and necroptosis. Additionally, growing evidence of crosstalk among these three pathways has led to the conceptualization of PANoptosis, an inflammatory cell death pathway that integrates components from other cell death pathways. The totality of biological effects in PANoptosis cannot be individually accounted for by pyroptosis, apoptosis, or necroptosis alone. Historically, apoptosis was considered to be the primary form of PCD employed in the CNS. Apoptosis is initiated by microenvironmental perturbations that result in initiator caspases (caspase-8 or -9) activating downstream executioner caspases (caspase-3, -6, and -7). In neurological diseases, markers of apoptotic cell death have been identified, including the presence of pro-apoptotic B-cell lymphoma-2 (Bcl-2) family members, the activation of caspases, and the cleavage of caspase substrates. However, nonapoptotic inflammatory PCD pathways also play a significant role in neurodegeneration. Pyroptosis is a proinflammatory, lytic PCD pathway that is associated with pathology in AD, multiple sclerosis, and traumatic brain injury. Canonical pyroptosis is a caspase-1–mediated cell death pathway that involves inflammasome formation and the activation and release of proinflammatory cytokines IL-1β and IL-18. Necroptosis, another lytic form of PCD that occurs in response to caspase-8 inhibition and is RIPK3- and MLKL-dependent, has also been shown to be involved in the pathophysiology of neurological diseases such as ALS, schizophrenia, and ischemia–reperfusion injury. The activation of RIPK1, a key inflammatory PCD molecule, may also lead to neuroinflammation and cell death.

6Many questions remain about the precise mechanisms through which innate immunity and PCD pathways modulate neuronal pathogenesis. Here, we discuss the link between neuroinflammation, innate immune responses, and AD. Innate immune sensors and molecular mechanisms of PCD, as related to AD, are also described, along with proposed AD therapeutic strategies targeting fundamental regulators of PCD. Considering the innate immune components of AD pathogenesis and identifying strategies to therapeutically target these pathways will be critical for informing clinical interventions.

2. Neuroinflammation, Innate Immunity, and AD: A Complex Relationship

7Neuroinflammation is involved in the propagation of several neurodegenerative disorders and has been shown to be a major contributor to AD pathogenesis and progression. Inflammation in the CNS can occur as a result of cells sensing Aβ or other damage- or pathogen-associated molecular patterns (DAMPs or PAMPs). Cells contain several pattern recognition receptors (PRRs), both on the cell surface and in the cytoplasm, that are responsible for recognizing DAMPs and PAMPs; sensing can induce inflammatory signaling pathways and immune responses. The five primary PRR families include Toll-like receptors (TLRs), retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), C-type lectin receptors (CLRs), and the absent in melanoma 2 (AIM2)-like receptors (ALRs). This PAMP/DAMP-mediated signaling response incites the production of inflammatory cytokines and chemokines, the induction of cell death to clear the infected cells, and in the case of AD, Tau protein misfolding or hyperphosphorylation and increased Aβ pathology. Inflammatory responses in the CNS are largely carried out by glial cells, including microglial cells and astrocytes, though endothelial cells also play a role. Below, we highlight the key molecular pathways involved in DAMP and PAMP sensing and cytokine release in these cell types.

2.1. Microglia

8Microglia are self-renewing immune cells of the CNS that arise from yolk-sac fetal macrophages. They play an essential role in regulating brain homeostasis and facilitating immune responses. Microglial cells patrol the environment, assess and maintain synaptic health, clear debris, and assist in neuronal survival. In response to stimuli, microglia can undergo classical activation to develop towards an M1 phenotype, which promotes inflammation, or they can undergo alternative/neuroprotective activation and develop towards an M2 phenotype, which is associated with anti-inflammatory functions. Healthy CNS maintenance requires a balance of M1 and M2 microglial activation to repair tissues, an M2 function, and also to clear cellular debris and aggregated misfolded proteins, an M1 function. While these functions are essential for homeostasis, the overactivation of these pathways can lead to pathology.

9Approximately 25% of the ~84 risk genes in AD that are associated with immune function have been identified to be enriched or exclusively expressed in microglia. Some of these genes are TREM2, CD33, INPP5D, CLU, CR1, SPI1, ABCA7, EPHA7, MS4As, HLA-DRB5-DRB1, CASP7, and CASP8 (Table 1). Further research is needed to understand how these specific risk variants impact protein function, which could aid in identifying therapeutic targets for AD treatment. In addition to these gene associations, several molecular mechanisms for innate immune activation in microglial cells have been implicated in AD pathogenesis. Microglia develop toward the proinflammatory M1 phenotype after sensing DAMPs and PAMPs through PRRs that include TLRs, RLRs, and NLRs. In neurodegenerative diseases such as AD, PRRs are highly expressed in microglia; signaling through PRRs can provoke an inflammatory response and proinflammatory cytokine secretion (Table 2). In healthy controls, activated microglia localize around Aβ plaques and neurons with NFTs. Microglia use cell surface receptors (CD14, TLR2, TLR4, α6β1 integrin, CD47) and scavenger receptors (CD36) to phagocytose and subsequently clear Aβ; specifically, the physical interaction of TLR2, TLR4, and the TLR4-coreceptor CD14 activates an immune response to fibrillar Aβ phagocytosis. While microglial activation is beneficial in preventing AD-associated pathology, the chronic activation of microglia is detrimental, as prolonged TLR2 and TLR4 activation in microglia induces Aβ production. If Aβ plaque formation is extensive, microglial cells cannot eliminate it. In a common AD mouse model where mice express the double transgenic APP/PS1 (chimeric mouse or human APP/human presenilin 1), the inhibition of TLR2 reduces glial cell reactivity, reduces Aβ, and improves cognitive function. Furthermore, TLR2/4-deficient C57BL/6 mice exhibit improved neuro-cognitive and behavioral patterns compared to wild-type mice in response to the Aβ1–42 peptide, and TLR2-deficient microglia induce proinflammatory cytokine release (TNF-α, IL-1β, IL-6) and enrich Aβ clearance. These results highlight the importance of TLRs in driving AD pathology.

10Other PRRs, such as inflammasome sensors, have also been associated with AD. Inflammasomes are multiprotein complexes that form in response to PAMP or DAMP sensing, and they generally contain a sensor, the adaptor protein ASC, and caspase-1. Several inflammasome sensors have been described, with the most well-characterized being the NLR family sensors, NLRP1, NLRP3, and NAIP/NLRC4, as well as other sensors containing pyrin domains, such as Pyrin and AIM2. The NLRP3 inflammasome, which has been implicated in autoinflammatory diseases, obesity, colitis, cancers, and infections, has emerged as a trigger of AD pathology. Tau can activate the NLRP3 inflammasome in microglia, inducing Tau pathology and potentiating AD pathogenesis. Similarly, NLRP3-deficient APP/PS1 mice are protected against neurobehavioral deficits and have reduced spatial memory deficits and Aβ buildup.

11In addition to the direct role of PRRs in AD pathogenesis, PRR activation and signaling in microglia can also induce the release of proinflammatory cytokines that drive pathology. Inflammation or injury to the neuron can activate microglia to generate proinflammatory factors (IL-1β, TNF-α, and IL-6; an M1 phenotype). Nucleic acid-containing Aβ elicits a TLR- and RLR-derived type I IFN response for C3-dependent synapse destruction. The expression of RIG-I, a key member of the RLR family, is elevated in the temporal cortex and plasma of patients with cognitive impairment. However, the mechanistic details of RIG-I involvement in AD pathogenesis have yet to be discovered.

12The activation of PRRs, especially inflammasome sensors, can lead to the release of IL-1β and IL-18, and these proinflammatory cytokines are also correlated with AD severity. Though the release of proinflammatory cytokines is a natural result of the aging process, their continuous release can lead to Aβ production and neuronal distress.

2.2. Astrocytes

13The CNS relies heavily on astrocytes for maintaining homeostasis and assisting with synapse formation and elimination. Astrocytes are more numerous than neurons and have a significant role in activation, neuroprotection, and neurotoxicity. They respond to cytokines/chemokines and can identify Aβ aggregates, undergo hypertrophy upon activation, and upregulate glial fibrillary acidic protein (GFAP) expression. Reactive astrocytes (atrophied or disrupted intralaminar astrocytes) are characteristically present in AD brains. While innate immune sensing in astrocytes is not well understood, inflammasome activation in astrocytes has been associated with some neurodegenerative diseases. The AIM2 inflammasome was found to be activated during experimental autoimmune encephalomyelitis in astrocytes, although these cells failed to undergo cell death and had poor IL-1β expression. Additionally, astroglial NLRP3 inflammasome complexes have also been reported to be involved in neuroinflammation in ALS, with higher levels of NLRP3, ASC, IL-18, and caspase-1 in comparison to non-diseased controls. The role of innate immunity in astrocytes during AD requires further characterization.

2.3. Endothelial Cells

14Single-nucleus transcriptome analyses from prefrontal cortical samples from patients with AD identified a variety of endothelial transcriptomic changes, specifically in angiogenesis and the immune response pathway when compared with healthy patients. The endothelial cells of AD patients showed an elevated expression of EGFL7, FLT1, and VWF (angiogenic growth factors and their receptors) and B2M and HLA-E (antigen presentation machinery), suggesting that these cells play a role in angiogenesis and immune responses in a diseased state. However, this cell type remains largely under-characterized for its roles in AD.

3. Cell Death and AD

15The major pathological hallmarks of AD include extracellular Aβ deposition, the intraneuronal aggregation of NFTs, and neuronal loss (neurodegeneration). In mammalian hosts, Aβ and Tau deposits act as DAMPs and are recognized by multiple PRRs, as discussed above (Table 2). The subsequent innate immune signaling can result in cell death, and these processes can provide significant protective responses against AD. Conversely, inflammatory cell death also releases proinflammatory cytokines and cellular contents that can stimulate severe inflammation. There is a delicate balance between an appropriate immune response, which clears Aβ and Tau deposits, and an exaggerated response, which promotes neuroinflammatory brain damage. Below, we discuss the mechanics of canonical PCD pathways and what is known about their involvement in AD.

3.1. Pyroptosis in AD

16Pyroptosis is an inflammatory PCD pathway initiated by the assembly of a multimeric protein complex called the inflammasome, as described above. The canonical inflammasome assembly cleaves pro–caspase-1, allowing its active form to cleave downstream substrates. These substrates include gasdermin D (GSDMD), leading to the release of its N-terminal fragment to form pores in the plasma membrane, and pro–IL-1β and pro–IL-18, which are processed into their active forms for release through the membrane pores. Since activated caspase-1 mediates potent cell death and an inflammatory response, its catalytic activity is under tight regulation.

17In pyroptosis, caspase-1-dependent GSDMD cleavage, and the subsequent release of IL-1β and IL-18, have been well characterized in immune cells such as macrophages. However, pyroptosis and inflammasome activation also occur in brain cells; activated caspase-1 is elevated in AD brains and in the APP/PS1 mouse model, and Aβ1-42 can induce pyroptosis in cortical neurons (Table 3). Additionally, Aβ fibrils can stimulate NLRP3 inflammasomes via lysosomal damage in mouse microglia. NLRP3 or caspase-1 deficiency in the APP/PS1 mouse model reduces spatial memory impairment, hippocampal synaptic plasticity loss, behavioral disturbances, and AD consequences. NLRP3 inflammasome deficiency also skews microglial cells from the M1 phenotype to the M2 phenotype. Furthermore, microglial cells have been shown to secrete IL-1β after NLRP3 activation with recombinant Tau protein. Together, these studies implicate pyroptosis in AD pathogenesis.

3.2. Apoptosis in AD

18Apoptosis occurs through either the extrinsic or intrinsic pathway. Extrinsic apoptosis is activated by extracellular stimuli through the formation of a death-inducing signaling complex (DISC) that recruits adaptor proteins (including TRADD and FADD) and pro-caspase-8. Caspase-8 can then activate effector caspases, caspase-3, -6 and -7, to drive further substrate cleavage and the execution of apoptotic cell death. Intrinsic apoptosis responds to intracellular changes in equilibrium and involves the activation of Bcl-2 family members followed by the release of mitochondrial proteins such as cytochrome c. Cytochrome c associates with APAF-1 and activates caspase-9, which enables downstream effectors, caspase-3, -6, and -7.

19Many studies have shown that compared to healthy brains, the expression profiles of several components of apoptosis, most notably the Bcl-2 family members, are altered in AD. Bcl-2 family members can be classified as either pro- or anti-apoptotic, with Bax, Bak, BAD, Bid, Bim, and Bcl-x being canonically pro-apoptotic and Bcl-2, Bcl-xL, and Mcl-1 being anti-apoptotic. Pro-apoptotic Bim is upregulated, anti-apoptotic Bcl-2 is downregulated, and pro-apoptotic Bax is activated in response to Aβ. Furthermore, anti-apoptotic Bcl-xL expressed in microglia has been shown to co-localize with Aβ deposits and activate astrocytes. Additionally, Bcl-2 proteins control intracellular calcium, and irregularities in calcium signaling have been implicated in AD progression, providing an additional link between apoptotic Bcl-2 proteins and AD.

20In addition to the Bcl-2 family members, apoptotic caspases are also associated with AD. Stimulating microglia with inflammogens can activate caspase-8, -3, and -7 in BV2 cells and in mice, and these caspases are activated in the microglia of patients with AD. Molecularly, caspase-3 can activate NF-κB, via protein kinase Cδ, and increase the production of neurotoxic proinflammatory mediators (IL-1β, TNF-α, and NO). Subsequently, in vitro inhibition of caspase-8 impedes microglia activation and neurotoxicity. Caspase-3 can cleave APP, and this cleavage event can provoke Aβ plaque formation and synaptic loss in the brain as well as cause noticeable changes in behavior. Along with caspase-3 activation, activating caspase-8 and -9 also induces Aβ plaque formation. From a therapeutic standpoint, the pan-caspase inhibitor (Q-VD-OPh) and microglial activation inhibitor (minocycline) have been shown to provide neuroprotective effects in TgCRND8 and APP/PS1 mouse models, respectively (Table 3). Collectively, these studies emphasize the involvement of apoptotic molecules in AD pathogenesis.

3.3. Necroptosis in AD

21Necroptosis can be initiated in response to multiple signaling pathways, including TLR signaling, death receptor engagement, and IFN signaling. The necroptotic cell death pathway is activated when caspase-8 is inhibited; RIPK1 is autophosphorylated and, through its interaction with phosphorylated RIPK3, recruits and phosphorylates MLKL. Oligomerized MLKL translocates to the plasma membrane where it interacts with phospholipids to produce membrane pores.

22Necroptosis can impair cognitive function; in the APP/PS1 mouse model, mice expressing constitutively active MLKL performed worse in the Morris water maze and had fewer neurons. In addition, a robust increase in the levels of RIPK1 and MLKL have been seen in AD brains compared to healthy controls (Table 3). Furthermore, inhibiting RIPK1 reduces Aβ deposits, inflammatory cytokines, and cognitive deficits in the APP/PS1 mouse model. There is also a correlation between necroptosis and reduced brain weight, which is a pathological consequence of AD. Additionally, aberrant protein phosphorylation is a well-recognized component of AD pathogenesis, and because the phosphorylation of RIPK1, RIPK3, and MLKL regulates necroptosis, it is possible that AD progression may modulate this cell death pathway.

3.4. PANoptosis in AD

23PCD pathways have long been thought of as segregated pathways with little overlap. However, numerous studies have found significant crosstalk among the components of pyroptosis, apoptosis, and necroptosis. Components of noninflammatory apoptosis can undergo crosstalk with molecules involved in executing lytic, inflammatory PCD pathways. For example, caspase-3 can activate GSDME, inducing a gasdermin-dependent cell death program, and caspase-8 can directly activate GSDMD in certain conditions. The culmination of the observed experimental crosstalk has led to the conceptualization of PANoptosis. PANoptosis is an inflammatory cell death pathway that integrates components from other cell death pathways. The totality of biological effects in PANoptosis cannot be individually accounted for by pyroptosis, apoptosis, or necroptosis alone. PANoptosis is regulated by multifaceted macromolecular complexes termed PANoptosomes. PANoptosis is initiated by PAMP/DAMP sensing through an upstream sensor, followed by assembly of the multi-protein PANoptosome complex. PANoptosis involves the activation of multiple cell death molecules, which can include caspase-1, gasdermins, caspase-8, caspase-3, caspase-7, caspase-6, MLKL, and potentially others. Molecules shown to be involved in PANoptosis, such as AIM2, caspase-8, caspase-1, RIPK3, and MLKL, have been implicated in neuroinflammation and neurodegenerative disorders, including AD (Table 1 and Table 3). Additionally, the increased expression of CASP1, CASP3, CASP6, CASP7, CASP8, and CASP9 have all been found in the entorhinal cortex of patients with AD with severe dementia, suggesting that pyroptosis or apoptosis alone may not account for the full picture of cell death in AD. Furthermore, inflammasome components are now well-established in their ability to drive PANoptotic cell death responses in mice in response to specific stimuli. To date, Z-DNA binding protein 1 (ZBP1)- and AIM2-PANoptosomes have been characterized, with more PANoptosomes likely to exist. In the context of AD, AIM2 deficiency has been shown to reduce Aβ deposition and microglial activation in the 5xFAD mouse model, suggesting that the AIM2-PANoptosome may play a role in AD. PANoptosis is an emerging concept which, when applied to AD, may allow for a more complete understanding of how PCD impacts AD and other neurodegenerative diseases.

4. Cytokines and Chemokines as Modulators of Neuroinflammation

24Innate immune signaling pathways and cell death mechanisms often culminate in the release of cytokines and chemokines. Cytokines, which are largely released by microglia and astrocytes, are major contributors of neuroinflammation. They are involved in chemoattraction, pro- and anti-inflammatory processes, neuronal injury, and the microglial response to Aβ deposits. Since cytokines modulate microglial activation, their presence or absence can be influential in the development and progression of AD (Table 4). Several disease conditions can release cytokines into the brain; this has been associated with dementia and the loss of neurocognition. For example, associations between dementia and infectious diseases have been reported. Additionally, high levels of intracranial proinflammatory cytokines have been reported during viral infections, including the neuroinvasive SARS-CoV-2, suggesting that these infections may also exacerbate neuroinflammation and promote disease. Recent evidence has also identified a mechanistic link between cytokine storms, particularly synergism between TNF-α and IFN-γ, and PANoptotic cell death, defining cytokine storms as a life-threatening condition caused by excessive production of cytokines mediated by inflammatory cell death, PANoptosis. Given the established role of TNF-α in AD and the links between cytokine storm and neuroinflammation, this process is likely to further contribute to AD pathology (Figure 1).

25Inflammation must be tightly balanced in the brain. A proinflammatory environment, such as that seen in AD brains, accounts for damaging pathology. The increased caspase-1 activation in AD leads to higher levels of IL-1β release; this can be detrimental if prolonged, but there are conditions where a slightly inflammatory environment can be beneficial. For instance, IL-1β expression activates a form of neuroinflammation in the APP/PS1 mouse model that reduces amyloid plaque pathology, suggesting that a low level of inflammatory cell death could help prevent AD pathology. However, those with mild cognitive impairment are at risk for conversion to AD if they have high levels of the proinflammatory cytokine TNF-α and decreased anti-inflammatory TGF-β in their cerebrospinal fluid (CSF). Neuronal function is impaired with elevated levels of IL-1β, TNF-α, and other cytokines, as shown by the suppression of long-term potentiation of synaptic transmission. Microglia in AD are skewed toward the M1 phenotype, indicated by a higher expression of proinflammatory cytokines/chemokines and innate immune receptors. Additionally in an AD mouse model (Mo/Hu APPswe PS1dE9 mice), TLR4 mediates higher levels of TNF-α and MIP-1α. Among the proinflammatory cytokines, interferon (IFN) is also a crucial molecule contributing to AD neuropathogenesis; RNA-seq data reported the upregulation of AD-related microglial-specific IFN-stimulated genes (ISGs) that had significant correlation with disease severity and complement activation.

26In addition to cytokines, chemokines also enhance local inflammation in AD by regulating microglial migration to areas of neuroinflammation. In AD, CCL2, CCR3, and CCR5 are elevated in reactive microglia, and CCL4 is detected in reactive astrocytes near the vicinity of Aβ plaques. Aβ treatment to human astrocytes and macrophages generates CXCL8 (IL-8), CCL2, CCL3, and CCL4, and microglia produce CXCL8, CCL2, and CCL3. Additionally, the CX3CR1/CX3CL1 AD mouse model modulates neuronal survival, plaque load, and cognition. Overall, cytokines and chemokines are important to modulate signaling to help clear DAMPs in the brain, but prolonged production and exposure contributes to pathology and disease in AD.

5. Therapeutic Implications of Innate Immune Involvement for AD Management

27Several AD therapeutics have attempted to target Aβ plaques and Tau. However, the clearance of Aβ plaques through anti-Aβ immunotherapy has failed to provide any cognitive benefit in patients with AD thus far. The U.S. FDA granted accelerated approval for aducanumab, an anti-Aβ immunotherapy, to be used in patients with AD; however, the drug remains highly controversial with two phase III trials providing conflicting clinical efficacy results and lingering concerns over safety. Previous anti-Tau therapies, such as those inhibiting kinases, Tau aggregation, or microtubule stabilization, have been withdrawn from clinical trials because of toxicity and efficacy issues. However, several current Tau-targeted immunotherapies, including AADvac-1, ABBV-8E12, BIIB092, and RO71015705, have shown promising preclinical results and are presently being evaluated in clinical trials; their efficacy in patients with AD remains to be determined. The overall lack of clinical success to date in targeting Aβ plaques and Tau has led to a critical need to identify alternative treatment strategies that target upstream signaling, such as innate immune processes and PCD.

28Mouse models, such as the APP/PS1 model as well as others, allow researchers to gain an understanding of relevant disease-related PCD signaling pathways and their regulation. The immediate hope is that PCD, in some capacity, can be targeted to modulate neurological disease severity and progression. However, this approach has also faced challenges. Historically, there has been an association between apoptosis and the expression of key apoptotic proteins with neurodegenerative disorders; yet in vivo targeting of apoptosis has failed to show effective therapeutic results. A recent clinical trial for minocycline, a 2nd generation tetracycline blocking cytochrome c release and upregulating Bcl-2 expression, was ineffective in patients with mild AD. This may be due in part to crosstalk between PCD pathways. In contrast, the pharmacological inhibition of RIPK1 to prevent necroptosis results in neuroprotection in preclinical AD models, suggesting that targeting cell death remains a potentially viable therapeutic strategy for AD. Therefore, several other clinical trials and preclinical studies involving compounds that target cell death molecules are currently ongoing (Table 5).

29A correlation has also been identified between inflammatory cytokines and their signaling pathways and AD, with microglia playing a key role in coupling inflammation with neurodegeneration. Therefore, neuroinflammatory biomarkers are also being evaluated as potential targets (Table 5). However, AD pathogenesis may also be prevented through the adaptive immune system and the regulation of microglial function.

30In addition to immune, inflammatory, and cell death pathways, the meningeal lymphatic vasculature (mLV) system may also be a promising therapeutic target for AD. The mLV system moves immune cells from the brain to the peripheral immune system; it is crucial in maintaining fluid homeostasis and enabling appropriate innate immune responses. Mice with altered mLV have worsening AD symptoms, and the photoablation of mLV in 5xFAD mice leads to increased Aβ deposition, neurovascular dysfunction, and cognitive defects. Dysfunctional mLV in murine models can also induce the activation of CNS immune cells and the increased secretion of proinflammatory cytokines IL-6, TNF-α, and IL-1β. These data suggest that mLV, through modulating inflammation, could be involved in the progression of neurodegenerative diseases such as AD and warrants further study to determine whether mLV could be considered as a therapeutic target.

6. Discussion and Future Directions

31Recent studies have significantly expanded our understanding of neuroinflammation, innate immune responses, and tightly orchestrated cell death signaling in AD pathogenesis. The brain immune cells (microglia) are integrally associated with innate immune cell death in AD pathology. Excessive neuroinflammation during Aβ and Tau clearance could be diminished by specifically regulating the innate immune cell death response. The continued elucidation of cell death pathways and the central innate immune sensor signaling pathways involved in regulating neuroinflammation and Aβ/Tau clearance will have a significant impact on the AD research field. The emerging concept of PANoptosis is likely to play a role in disease pathogenesis and understanding its relevance in AD therapeutics. Emerging AD studies are focusing on this network of inflammasomes, inflammatory cell death, and neuroinflammation. Further investigations into these processes will potentially aid in identifying novel therapeutic targets for AD management.

References 249

1.
Global, regional, and national burden of Alzheimer's disease and other dementias, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016 · 2019
No notice
2.
Maccioni R.B., Rojo L.E., Fernández J.A., Kuljis R.O. The role of neuroimmunomodulation in Alzheimer’s disease. Ann. N. Y. Acad. Sci. 2009;1153:240-246.
Not in our library10.1111/j.1749-6632.2008.03972.x
3.
Jiang C., Zou X., Zhu R., Shi Y., Wu Z., Zhao F., Chen L. The correlation between accumulation of amyloid beta with enhanced neuroinflammation and cognitive impairment after intraventricular hemorrhage. J. Neurosurg. 2018;131:54-63.
Not in our library10.3171/2018.1.jns172938
4.
Molecular mechanisms of cell death in neurological diseases · 2021
No notice
5.
Jack C.R., Knopman D.S., Jagust W.J., Shaw L.M., Aisen P.S., Weiner M.W., Petersen R.C., Trojanowski J.Q. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol. 2010;9:119-128.
Not in our library10.1016/s1474-4422(09)70299-6
6.
Chen G.F., Xu T.H., Yan Y., Zhou Y.R., Jiang Y., Melcher K., Xu H.E. Amyloid beta: Structure, biology and structure-based therapeutic development. Acta. Pharm. Sin. 2017;38:1205-1235.
Not in our library10.1038/aps.2017.28
7.
Chasseigneaux S., Allinquant B. Functions of Abeta, sAPPalpha and sAPPbeta: Similarities and differences. J. Neurochem. 2012;120((Suppl. S1)):99-108.
Not in our library10.1111/j.1471-4159.2011.07584.x
8.
Katzmarski N., Ziegler-Waldkirch S., Scheffler N., Witt C., Abou-Ajram C., Nuscher B., Prinz M., Haass C., Meyer-Luehmann M. Abeta oligomers trigger and accelerate Abeta seeding. Brain Pathol. 2020;30:36-45.
Not in our library10.1111/bpa.12734
9.
Heneka M.T., Carson M.J., El Khoury J., Landreth G.E., Brosseron F., Feinstein D.L., Jacobs A.H., Wyss-Coray T., Vitorica J., Ransohoff R.M., et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14:388-405.
Not in our library10.1016/s1474-4422(15)70016-5
10.
Wesseling H., Mair W., Kumar M., Schlaffner C.N., Tang S., Beerepoot P., Fatou B., Guise A.J., Cheng L., Takeda S., et al. Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease. Cell. 2020;183:1699-1713.e13.
Not in our library10.1016/j.cell.2020.10.029
11.
Hyperphosphorylation of Tau Associates With Changes in Its Function Beyond Microtubule Stability · 2018
No notice
12.
Fiandaca M.S., Kapogiannis D., Mapstone M., Boxer A., Eitan E., Schwartz J.B., Abner E.L., Petersen R.C., Federoff H.J., Miller B.L., et al. Identification of preclinical Alzheimer’s disease by a profile of pathogenic proteins in neurally derived blood exosomes: A case-control study. Alzheimers Dement. 2015;11:600-607.e1.
Not in our library10.1016/j.jalz.2014.06.008
13.
Jia L., Qiu Q., Zhang H., Chu L., Du Y., Zhang J., Zhou C., Liang F., Shi S., Wang S., et al. Concordance between the assessment of Abeta42, T-tau, and P-T181-tau in peripheral blood neuronal-derived exosomes and cerebrospinal fluid. Alzheimers Dement. 2019;15:1071-1080.
Not in our library10.1016/j.jalz.2019.05.002
14.
Cortes N., Andrade V., Guzman-Martinez L., Estrella M., Maccioni R.B. Neuroimmune Tau Mechanisms: Their Role in the Progression of Neuronal Degeneration. Int. J. Mol. Sci. 2018;19:956.
Not in our library10.3390/ijms19040956
15.
Weingarten M.D., Lockwood A.H., Hwo S.Y., Kirschner M.W. A protein factor essential for microtubule assembly. Proc. Natl. Acad. Sci. USA. 1975;72:1858-1862.
Not in our library10.1073/pnas.72.5.1858
16.
Drechsel D.N., Hyman A.A., Cobb M.H., Kirschner M.W. Modulation of the dynamic instability of tubulin assembly by the microtubule-associated protein tau. Mol. Biol. Cell. 1992;3:1141-1154.
Not in our library10.1091/mbc.3.10.1141
17.
Galluzzi L., Vitale I., Aaronson S.A., Abrams J.M., Adam D., Agostinis P., Alnemri E.S., Altucci L., Amelio I., Andrews D.W., et al. Molecular mechanisms of cell death: Recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018;25:486-541.
Not in our library10.1038/s41418-017-0012-4
18.
Kuriakose T., Man S.M., Malireddi R.K., Karki R., Kesavardhana S., Place D.E., Neale G., Vogel P., Kanneganti T.D. ZBP1/DAI is an innate sensor of influenza virus triggering the NLRP3 inflammasome and programmed cell death pathways. Sci. Immunol. 2016;1:aag2045.
Not in our library10.1126/sciimmunol.aag2045
19.
Malireddi R.K.S., Karki R., Sundaram B., Kancharana B., Lee S., Samir P., Kanneganti T.D. Inflammatory Cell Death, PANoptosis, Mediated by Cytokines in Diverse Cancer Lineages Inhibits Tumor Growth. Immunohorizons. 2021;5:568-580.
Not in our library10.4049/immunohorizons.2100059
20.
Kesavardhana S., Malireddi R.K.S., Burton A.R., Porter S.N., Vogel P., Pruett-Miller S.M., Kanneganti T.-D. The Zα2 domain of ZBP1 is a molecular switch regulating influenza-induced PANoptosis and perinatal lethality during development. J. Biol. Chem. 2020;295:8325-8330.
Not in our library10.1074/jbc.ra120.013752
21.
ZBP1 promotes fungi-induced inflammasome activation and pyroptosis, apoptosis, and necroptosis (PANoptosis) · 2020
No notice
22.
Identification of the PANoptosome: A Molecular Platform Triggering Pyroptosis, Apoptosis, and Necroptosis (PANoptosis) · 2020
No notice
23.
Karki R., Sharma B.R., Lee E., Banoth B., Malireddi R.K.S., Samir P., Tuladhar S., Mummareddy H., Burton A.R., Vogel P., et al. Interferon regulatory factor 1 regulates PANoptosis to prevent colorectal cancer. JCI Insight. 2020;5.
Not in our library10.1172/jci.insight.136720
24.
Impaired NLRP3 inflammasome activation/pyroptosis leads to robust inflammatory cell death via caspase-8/RIPK3 during coronavirus infection · 2020
No notice
25.
Gurung P., Burton A., Kanneganti T.D. NLRP3 inflammasome plays a redundant role with caspase 8 to promote IL-1beta-mediated osteomyelitis. Proc. Natl. Acad. Sci. USA. 2016;113:4452-4457.
Not in our library10.1073/pnas.1601636113
26.
Lukens J.R., Gurung P., Vogel P., Johnson G.R., Carter R.A., McGoldrick D.J., Bandi S.R., Calabrese C.R., Vande Walle L., Lamkanfi M., et al. Dietary modulation of the microbiome affects autoinflammatory disease. Nature. 2014;516:246-249.
Not in our library10.1038/nature13788
27.
Malireddi R.K., Ippagunta S., Lamkanfi M., Kanneganti T.D. Cutting edge: Proteolytic inactivation of poly(ADP-ribose) polymerase 1 by the Nlrp3 and Nlrc4 inflammasomes. J. Immunol. 2010;185:3127-3130.
Not in our library10.4049/jimmunol.1001512
28.
Malireddi R.K.S., Gurung P., Kesavardhana S., Samir P., Burton A., Mummareddy H., Vogel P., Pelletier S., Burgula S., Kanneganti T.D. Innate immune priming in the absence of TAK1 drives RIPK1 kinase activity-independent pyroptosis, apoptosis, necroptosis, and inflammatory disease. J. Exp. Med. 2020;217.
Not in our library10.1084/jem.20191644
29.
Malireddi R.K.S., Kesavardhana S., Karki R., Kancharana B., Burton A.R., Kanneganti T.D. RIPK1 Distinctly Regulates Yersinia-Induced Inflammatory Cell Death, PANoptosis. Immunohorizons. 2020;4:789-796.
Not in our library10.4049/immunohorizons.2000097
30.
Zheng M., Karki R., Vogel P., Kanneganti T.D. Caspase-6 is a key regulator of innate immunity, inflammasome activation and host defense. Cell. 2020;181:674-687.e13.
Not in our library10.1016/j.cell.2020.03.040
31.
Karki R., Sharma B.R., Tuladhar S., Williams E.P., Zalduondo L., Samir P., Zheng M., Sundaram B., Banoth B., Malireddi R.K.S., et al. Synergism of TNF-alpha and IFN-gamma Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes. Cell. 2021;184:149-168.e17.
Not in our library10.1016/j.cell.2020.11.025
32.
Malireddi R.K.S., Gurung P., Mavuluri J., Dasari T.K., Klco J.M., Chi H., Kanneganti T.D. TAK1 restricts spontaneous NLRP3 activation and cell death to control myeloid proliferation. J. Exp. Med. 2018;215:1023-1034.
Not in our library10.1084/jem.20171922
33.
Lamkanfi M., Kanneganti T.D., Van Damme P., Vanden Berghe T., Vanoverberghe I., Vandekerckhove J., Vandenabeele P., Gevaert K., Nunez G. Targeted peptidecentric proteomics reveals caspase-7 as a substrate of the caspase-1 inflammasomes. Mol. Cell Proteom. 2008;7:2350-2363.
Not in our library10.1074/mcp.m800132-mcp200
34.
Gurung P., Anand P.K., Malireddi R.K., Vande Walle L., Van Opdenbosch N., Dillon C.P., Weinlich R., Green D.R., Lamkanfi M., Kanneganti T.D. FADD and caspase-8 mediate priming and activation of the canonical and noncanonical Nlrp3 inflammasomes. J. Immunol. 2014;192:1835-1846.
Not in our library10.4049/jimmunol.1302839
35.
AIM2 forms a complex with pyrin and ZBP1 to drive PANoptosis and host defence · 2021
No notice
36.
Karki R., Sundaram B., Sharma B.R., Lee S., Malireddi R.K.S., Nguyen L.N., Christgen S., Zheng M., Wang Y., Samir P., et al. ADAR1 restricts ZBP1-mediated immune response and PANoptosis to promote tumorigenesis. Cell Rep. 2021;37:109858.
Not in our library10.1016/j.celrep.2021.109858
37.
Mattson M.P. Apoptosis in neurodegenerative disorders. Nat. Rev. Mol. Cell Biol. 2000;1:120-129.
Not in our library10.1038/35040009
38.
McKenzie B.A., Dixit V.M., Power C. Fiery Cell Death: Pyroptosis in the Central Nervous System. Trends Neurosci. 2020;43:55-73.
Not in our library10.1016/j.tins.2019.11.005
39.
Cookson B.T., Brennan M.A. Pro-inflammatory programmed cell death. Trends Microbiol. 2001;9:113-114.
Not in our library10.1016/s0966-842x(00)01936-3
40.
Martinon F., Burns K., Tschopp J. The inflammasome: A molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol. Cell. 2002;10:417-426.
Not in our library10.1016/s1097-2765(02)00599-3
41.
The role of necroptosis in cancer biology and therapy · 2019
No notice
42.
Necroptosis in anti-viral inflammation · 2018
No notice
43.
Kang T.B., Ben-Moshe T., Varfolomeev E.E., Pewzner-Jung Y., Yogev N., Jurewicz A., Waisman A., Brenner O., Haffner R., Gustafsson E., et al. Caspase-8 serves both apoptotic and nonapoptotic roles. J. Immunol. 2004;173:2976-2984.
Not in our library10.4049/jimmunol.173.5.2976
44.
Shan B., Pan H., Najafov A., Yuan J. Necroptosis in development and diseases. Genes Dev. 2018;32:327-340.
Not in our library10.1101/gad.312561.118
45.
Ofengeim D., Yuan J. Regulation of RIP1 kinase signalling at the crossroads of inflammation and cell death. Nat. Rev. Mol. Cell Biol. 2013;14:727-736.
Not in our library10.1038/nrm3683
46.
Weinlich R., Oberst A., Beere H.M., Green D.R. Necroptosis in development, inflammation and disease. Nat. Rev. Mol. Cell Biol. 2017;18:127-136.
Not in our library10.1038/nrm.2016.149
47.
Kanneganti T.D. Intracellular innate immune receptors: Life inside the cell. Immunol Rev. 2020;297:5-12.
Not in our library10.1111/imr.12912
48.
Norris G.T., Kipnis J. Immune cells and CNS physiology: Microglia and beyond. J. Exp. Med. 2019;216:60-70.
Not in our library10.1084/jem.20180199
49.
Ajami B., Bennett J.L., Krieger C., Tetzlaff W., Rossi F.M. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat. Neurosci. 2007;10:1538-1543.
Not in our library10.1038/nn2014
50.
Tay T.L., Hagemeyer N., Prinz M. The force awakens: Insights into the origin and formation of microglia. Curr. Opin. Neurobiol. 2016;39:30-37.
Not in our library10.1016/j.conb.2016.04.003
51.
Elmore M.R., Najafi A.R., Koike M.A., Dagher N.N., Spangenberg E.E., Rice R.A., Kitazawa M., Matusow B., Nguyen H., West B.L., et al. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron. 2014;82:380-397.
Not in our library10.1016/j.neuron.2014.02.040
52.
Alzheimer's Disease: The Role of Microglia in Brain Homeostasis and Proteopathy · 2017
No notice
53.
Hanisch U.K., Kettenmann H. Microglia: Active sensor and versatile effector cells in the normal and pathologic brain. Nat. Neurosci. 2007;10:1387-1394.
Not in our library10.1038/nn1997
54.
Microglia and Beyond: Innate Immune Cells As Regulators of Brain Development and Behavioral Function · 2018
No notice
55.
Inflammatory Response in the CNS: Friend or Foe? · 2016
No notice
56.
Age and Age-Related Diseases: Role of Inflammation Triggers and Cytokines · 2018
No notice
57.
Hodges A.K., Piers T.M., Collier D., Cousins O., Pocock J.M. Pathways linking Alzheimer’s disease risk genes expressed highly in microglia. Neuroimmunol. Neuroinflammation. 2021;8:245-268.
Not in our library10.20517/2347-8659.2020.60
58.
Baroja-Mazo A., Martin-Sanchez F., Gomez A.I., Martinez C.M., Amores-Iniesta J., Compan V., Barbera-Cremades M., Yague J., Ruiz-Ortiz E., Anton J., et al. The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nat. Immunol. 2014;15:738-748.
Not in our library10.1038/ni.2919
59.
Koenigsknecht-Talboo J., Landreth G.E. Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines. J. Neurosci. 2005;25:8240-8249.
Not in our library10.1523/jneurosci.1808-05.2005
60.
Beta amyloid oligomers and fibrils stimulate differential activation of primary microglia · 2009
No notice
61.
Kigerl K.A., de Rivero Vaccari J.P., Dietrich W.D., Popovich P.G., Keane R.W. Pattern recognition receptors and central nervous system repair. Exp. Neurol. 2014;258:5-16.
Not in our library10.1016/j.expneurol.2014.01.001
62.
Heneka M.T., Kummer M.P., Latz E. Innate immune activation in neurodegenerative disease. Nat. Rev. Immunol. 2014;14:463-477.
Not in our library10.1038/nri3705
63.
McDonough A., Lee R.V., Weinstein J.R. Microglial Interferon Signaling and White Matter. Neurochem. Res. 2017;42:2625-2638.
Not in our library10.1007/s11064-017-2307-8
64.
Nagele R.G., Wegiel J., Venkataraman V., Imaki H., Wang K.C., Wegiel J. Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease. Neurobiol. Aging. 2004;25:663-674.
Not in our library10.1016/j.neurobiolaging.2004.01.007
65.
Serrano-Pozo A., Mielke M.L., Gomez-Isla T., Betensky R.A., Growdon J.H., Frosch M.P., Hyman B.T. Reactive glia not only associates with plaques but also parallels tangles in Alzheimer’s disease. Am. J. Pathol. 2011;179:1373-1384.
Not in our library10.1016/j.ajpath.2011.05.047
66.
Bamberger M.E., Harris M.E., McDonald D.R., Husemann J., Landreth G.E. A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation. J. Neurosci. 2003;23:2665-2674.
Not in our library10.1523/jneurosci.23-07-02665.2003
67.
Mechanisms of Aβ Clearance and Degradation by Glial Cells · 2016
No notice
68.
Tahara K., Kim H.D., Jin J.J., Maxwell J.A., Li L., Fukuchi K. Role of toll-like receptor signalling in Abeta uptake and clearance. Brain. 2006;129:3006-3019.
Not in our library10.1093/brain/awl249
69.
Microglial Scavenger Receptors and Their Roles in the Pathogenesis of Alzheimer's Disease · 2012
No notice
70.
Reed-Geaghan E.G., Savage J.C., Hise A.G., Landreth G.E. CD14 and toll-like receptors 2 and 4 are required for fibrillar A{beta}-stimulated microglial activation. J. Neurosci. 2009;29:11982-11992.
Not in our library10.1523/jneurosci.3158-09.2009
71.
Chen K., Iribarren P., Hu J., Chen J., Gong W., Cho E.H., Lockett S., Dunlop N.M., Wang J.M. Activation of Toll-like receptor 2 on microglia promotes cell uptake of Alzheimer disease-associated amyloid beta peptide. J. Biol. Chem. 2006;281:3651-3659.
Not in our library10.1074/jbc.m508125200
72.
Hickman S.E., Allison E.K., El Khoury J. Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer’s disease mice. J. Neurosci. 2008;28:8354-8360.
Not in our library10.1523/jneurosci.0616-08.2008
73.
The dynamics of monocytes and microglia in Alzheimer’s disease · 2015
No notice
74.
Frackowiak J., Wisniewski H.M., Wegiel J., Merz G.S., Iqbal K., Wang K.C. Ultrastructure of the microglia that phagocytose amyloid and the microglia that produce beta-amyloid fibrils. Acta Neuropathol. 1992;84:225-233.
Not in our library10.1007/bf00227813
75.
Functional Impairment of Microglia Coincides with Beta-Amyloid Deposition in Mice with Alzheimer-Like Pathology · 2013
No notice
76.
Lok K., Zhao H., Shen H., Wang Z., Gao X., Zhao W., Yin M. Characterization of the APP/PS1 mouse model of Alzheimer’s disease in senescence accelerated background. Neurosci. Lett. 2013;557:84-89.
Not in our library10.1016/j.neulet.2013.10.051
77.
McDonald C.L., Hennessy E., Rubio-Araiz A., Keogh B., McCormack W., McGuirk P., Reilly M., Lynch M.A. Inhibiting TLR2 activation attenuates amyloid accumulation and glial activation in a mouse model of Alzheimer’s disease. Brain Behav. Immun. 2016;58:191-200.
Not in our library10.1016/j.bbi.2016.07.143
78.
Vollmar P., Kullmann J.S., Thilo B., Claussen M.C., Rothhammer V., Jacobi H., Sellner J., Nessler S., Korn T., Hemmer B. Active immunization with amyloid-beta 1-42 impairs memory performance through TLR2/4-dependent activation of the innate immune system. J. Immunol. 2010;185:6338-6347.
Not in our library10.4049/jimmunol.1001765
79.
Jana M., Palencia C.A., Pahan K. Fibrillar amyloid-beta peptides activate microglia via TLR2: Implications for Alzheimer’s disease. J. Immunol. 2008;181:7254-7262.
Not in our library10.4049/jimmunol.181.10.7254
80.
Liu S., Liu Y., Hao W., Wolf L., Kiliaan A.J., Penke B., Rube C.E., Walter J., Heneka M.T., Hartmann T., et al. TLR2 is a primary receptor for Alzheimer’s amyloid beta peptide to trigger neuroinflammatory activation. J. Immunol. 2012;188:1098-1107.
Not in our library10.4049/jimmunol.1101121
81.
Griciuc A., Tanzi R.E. The role of innate immune genes in Alzheimer’s disease. Curr. Opin. Neurol. 2021;34:228-236.
Not in our library10.1097/wco.0000000000000911
82.
Wightman D.P., Jansen I.E., Savage J.E., Shadrin A.A., Bahrami S., Holland D., Rongve A., Borte S., Winsvold B.S., Drange O.K., et al. A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease. Nat. Genet. 2021;53:1276-1282.
Not in our library10.1038/s41588-021-00921-z
83.
Chatila Z.K., Bradshaw E.M. Alzheimer’s Disease Genetics: A Dampened Microglial Response? Neuroscientist. 2021;10738584211024531.
Not in our library10.1177/10738584211024531
84.
Boutajangout A., Wisniewski T. The innate immune system in Alzheimer’s disease. Int. J. Cell Biol. 2013;2013:576383.
Not in our library10.1155/2013/576383
85.
Takatori S., Wang W., Iguchi A., Tomita T. Genetic Risk Factors for Alzheimer Disease: Emerging Roles of Microglia in Disease Pathomechanisms. Advances in Experimental Medicine and Biology. 2019;Volume 1118.
Not in our library10.1007/978-3-030-05542-4_5
86.
TLR4 mutation reduces microglial activation, increases Aβ deposits and exacerbates cognitive deficits in a mouse model of Alzheimer's disease · 2011
No notice
87.
Kaushal V., Dye R., Pakavathkumar P., Foveau B., Flores J., Hyman B., Ghetti B., Koller B.H., LeBlanc A.C. Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-beta production and axonal degeneration-associated Caspase-6 activation. Cell Death Differ. 2015;22:1676-1686.
Not in our library10.1038/cdd.2015.16
88.
Heneka M.T., Kummer M.P., Stutz A., Delekate A., Schwartz S., Vieira-Saecker A., Griep A., Axt D., Remus A., Tzeng T.C., et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature. 2013;493:674-678.
Not in our library10.1038/nature11729
89.
Freeman L., Guo H., David C.N., Brickey W.J., Jha S., Ting J.P. NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes. J. Exp. Med. 2017;214:1351-1370.
Not in our library10.1084/jem.20150237
90.
Wu P.J., Hung Y.F., Liu H.Y., Hsueh Y.P. Deletion of the Inflammasome Sensor Aim2 Mitigates Abeta Deposition and Microglial Activation but Increases Inflammatory Cytokine Expression in an Alzheimer Disease Mouse Model. Neuroimmunomodulation. 2017;24:29-39.
Not in our library10.1159/000477092
91.
Wang Y., Cella M., Mallinson K., Ulrich J.D., Young K.L., Robinette M.L., Gilfillan S., Krishnan G.M., Sudhakar S., Zinselmeyer B.H., et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell. 2015;160:1061-1071.
Not in our library10.1016/j.cell.2015.01.049
92.
Cheng J., Liao Y., Xiao L., Wu R., Zhao S., Chen H., Hou B., Zhang X., Liang C., Xu Y., et al. Autophagy regulates MAVS signaling activation in a phosphorylation-dependent manner in microglia. Cell Death Differ. 2017;24:276-287.
Not in our library10.1038/cdd.2016.121
93.
Paula Martorell V.B., Schwarz S., Heneka M. cGAS-STING activation in Alzheimer’s disease.
Not in our library
94.
De Rivero Vaccari J.P., Brand F.J., Sedaghat C., Mash D.C., Dietrich W.D., Keane R.W. RIG-1 receptor expression in the pathology of Alzheimer’s disease. J. Neuroinflammation. 2014;11:67.
Not in our library10.1186/1742-2094-11-67
95.
Kanneganti T.D., Ozoren N., Body-Malapel M., Amer A., Park J.H., Franchi L., Whitfield J., Barchet W., Colonna M., Vandenabeele P., et al. Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature. 2006;440:233-236.
Not in our library10.1038/nature04517
96.
Mariathasan S., Weiss D.S., Newton K., McBride J., O’Rourke K., Roose-Girma M., Lee W.P., Weinrauch Y., Monack D.M., Dixit V.M. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature. 2006;440:228-232.
Not in our library10.1038/nature04515
97.
Martinon F., Petrilli V., Mayor A., Tardivel A., Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440:237-241.
Not in our library10.1038/nature04516
98.
Franchi L., Amer A., Body-Malapel M., Kanneganti T.D., Ozoren N., Jagirdar R., Inohara N., Vandenabeele P., Bertin J., Coyle A., et al. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in salmonella-infected macrophages. Nat. Immunol. 2006;7:576-582.
Not in our library10.1038/ni1346
99.
Miao E.A., Alpuche-Aranda C.M., Dors M., Clark A.E., Bader M.W., Miller S.I., Aderem A. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf. Nat. Immunol. 2006;7:569-575.
Not in our library10.1038/ni1344
100.
Mariathasan S., Newton K., Monack D.M., Vucic D., French D.M., Lee W.P., Roose-Girma M., Erickson S., Dixit V.M. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature. 2004;430:213-218.
Not in our library10.1038/nature02664
101.
Xu H., Yang J., Gao W., Li L., Li P., Zhang L., Gong Y.N., Peng X., Xi J.J., Chen S., et al. Innate immune sensing of bacterial modifications of Rho GTPases by the Pyrin inflammasome. Nature. 2014;513:237-241.
Not in our library10.1038/nature13449
102.
Fernandes-Alnemri T., Yu J.W., Datta P., Wu J., Alnemri E.S. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature. 2009;458:509-513.
Not in our library10.1038/nature07710
103.
Hornung V., Ablasser A., Charrel-Dennis M., Bauernfeind F., Horvath G., Caffrey D.R., Latz E., Fitzgerald K.A. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature. 2009;458:514-518.
Not in our library10.1038/nature07725
104.
Sharma B.R., Kanneganti T.D. NLRP3 inflammasome in cancer and metabolic diseases. Nat. Immunol. 2021;22:550-559.
Not in our library10.1038/s41590-021-00886-5
105.
Aggregated Tau activates NLRP3–ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo · 2019
No notice
106.
Roy E.R., Wang B., Wan Y.W., Chiu G., Cole A., Yin Z., Propson N.E., Xu Y., Jankowsky J.L., Liu Z., et al. Type I interferon response drives neuroinflammation and synapse loss in Alzheimer disease. J. Clin. Investig. 2020;130:1912-1930.
Not in our library10.1172/jci133737
107.
Forlenza O.V., Diniz B.S., Talib L.L., Mendonca V.A., Ojopi E.B., Gattaz W.F., Teixeira A.L. Increased serum IL-1beta level in Alzheimer’s disease and mild cognitive impairment. Dement. Geriatr. Cogn. Disord. 2009;28:507-512.
Not in our library10.1159/000255051
108.
Peripheral inflammation in prodromal Alzheimer’s and Lewy body dementias · 2017
No notice
109.
Ojala J., Alafuzoff I., Herukka S.K., van Groen T., Tanila H., Pirttila T. Expression of interleukin-18 is increased in the brains of Alzheimer’s disease patients. Neurobiol. Aging. 2009;30:198-209.
Not in our library10.1016/j.neurobiolaging.2007.06.006
110.
IL-1β, IL-6, TNF- α and CRP in Elderly Patients with Depression or Alzheimer’s disease: Systematic Review and Meta-Analysis · 2018
No notice
111.
Hansen D.V., Hanson J.E., Sheng M. Microglia in Alzheimer’s disease. J. Cell Biol. 2018;217:459-472.
Not in our library10.1083/jcb.201709069
112.
Microglia in Alzheimer Disease: Well-Known Targets and New Opportunities · 2019
No notice
113.
Sarlus H., Heneka M.T. Microglia in Alzheimer’s disease. J. Clin. Investig. 2017;127:3240-3249.
Not in our library10.1172/jci90606
114.
Tejera D., Heneka M.T. Microglia in Alzheimer’s disease: The good, the bad and the ugly. Curr. Alzheimer Res. 2016;13:370-380.
Not in our library10.2174/1567205013666151116125012
115.
Wyss-Coray T., Rogers J. Inflammation in Alzheimer disease-a brief review of the basic science and clinical literature. Cold Spring Harb Perspect Med. 2012;2:a006346.
Not in our library10.1101/cshperspect.a006346
116.
Biber K., Neumann H., Inoue K., Boddeke H.W. Neuronal ‘On’ and ‘Off’ signals control microglia. Trends Neurosci. 2007;30:596-602.
Not in our library10.1016/j.tins.2007.08.007
117.
Verkhratsky A., Nedergaard M. Physiology of Astroglia. Physiol. Rev. 2018;98:239-389.
Not in our library10.1152/physrev.00042.2016
118.
Astrocytes in Alzheimer’s Disease: Pathological Significance and Molecular Pathways · 2021
No notice
119.
Chung W.S., Allen N.J., Eroglu C. Astrocytes Control Synapse Formation, Function, and Elimination. Cold Spring Harb. Perspect. Biol. 2015;7:a020370.
Not in our library10.1101/cshperspect.a020370
120.
Sheeler C., Rosa J.G., Ferro A., McAdams B., Borgenheimer E., Cvetanovic M. Glia in Neurodegeneration: The Housekeeper, the Defender and the Perpetrator. Int. J. Mol. Sci. 2020;21:9188.
Not in our library10.3390/ijms21239188
121.
Gamage R., Wagnon I., Rossetti I., Childs R., Niedermayer G., Chesworth R., Gyengesi E. Cholinergic Modulation of Glial Function During Aging and Chronic Neuroinflammation. Front. Cell Neurosci. 2020;14:577912.
Not in our library10.3389/fncel.2020.577912
122.
Linnerbauer M., Wheeler M.A., Quintana F.J. Astrocyte Crosstalk in CNS Inflammation. Neuron. 2020;108:608-622.
Not in our library10.1016/j.neuron.2020.08.012
123.
Giovannoni F., Quintana F.J. The Role of Astrocytes in CNS Inflammation. Trends Immunol. 2020;41:805-819.
Not in our library10.1016/j.it.2020.07.007
124.
Hol E.M., Pekny M. Glial fibrillary acidic protein (GFAP) and the astrocyte intermediate filament system in diseases of the central nervous system. Curr. Opin. Cell Biol. 2015;32:121-130.
Not in our library10.1016/j.ceb.2015.02.004
125.
Neuroinflammation in Alzheimer’s Disease · 2021
No notice
126.
Barclay W.E., Aggarwal N., Deerhake M.E., Inoue M., Nonaka T., Nozaki K., Luzum N.A., Miao E.A., Shinohara M.L. The AIM2 inflammasome is activated in astrocytes during the late phase of EAE. JCI Insight. 2022;7.
Not in our library10.1172/jci.insight.155563
127.
Johann S., Heitzer M., Kanagaratnam M., Goswami A., Rizo T., Weis J., Troost D., Beyer C. NLRP3 inflammasome is expressed by astrocytes in the SOD1 mouse model of ALS and in human sporadic ALS patients. Glia. 2015;63:2260-2273.
Not in our library10.1002/glia.22891
128.
Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer’s disease · 2020
No notice
129.
Nelson P.T., Alafuzoff I., Bigio E.H., Bouras C., Braak H., Cairns N.J., Castellani R.J., Crain B.J., Davies P., Del Tredici K., et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: A review of the literature. J. Neuropathol. Exp. Neurol. 2012;71:362-381.
Not in our library10.1097/nen.0b013e31825018f7
130.
Ising C., Venegas C., Zhang S., Scheiblich H., Schmidt S.V., Vieira-Saecker A., Schwartz S., Albasset S., McManus R.M., Tejera D., et al. NLRP3 inflammasome activation drives tau pathology. Nature. 2019;575:669-673.
Not in our library10.1038/s41586-019-1769-z
131.
Venegas C., Kumar S., Franklin B.S., Dierkes T., Brinkschulte R., Tejera D., Vieira-Saecker A., Schwartz S., Santarelli F., Kummer M.P., et al. Microglia-derived ASC specks cross-seed amyloid-beta in Alzheimer’s disease. Nature. 2017;552:355-361.
Not in our library10.1038/nature25158
132.
Bergsbaken T., Fink S.L., Cookson B.T. Pyroptosis: Host cell death and inflammation. Nat. Rev. Microbiol. 2009;7:99-109.
Not in our library10.1038/nrmicro2070
133.
Pasparakis M., Vandenabeele P. Necroptosis and its role in inflammation. Nature. 2015;517:311-320.
Not in our library10.1038/nature14191
134.
Ding J., Wang K., Liu W., She Y., Sun Q., Shi J., Sun H., Wang D.C., Shao F. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature. 2016;535:111-116.
Not in our library10.1038/nature18590
135.
Liu X., Zhang Z., Ruan J., Pan Y., Magupalli V.G., Wu H., Lieberman J. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature. 2016;535:153-158.
Not in our library10.1038/nature18629
136.
Sborgi L., Ruhl S., Mulvihill E., Pipercevic J., Heilig R., Stahlberg H., Farady C.J., Muller D.J., Broz P., Hiller S. GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death. EMBO J. 2016;35:1766-1778.
Not in our library10.15252/embj.201694696
137.
He W.T., Wan H., Hu L., Chen P., Wang X., Huang Z., Yang Z.H., Zhong C.Q., Han J. Gasdermin D is an executor of pyroptosis and required for interleukin-1beta secretion. Cell Res. 2015;25:1285-1298.
Not in our library10.1038/cr.2015.139
138.
Shi J., Zhao Y., Wang K., Shi X., Wang Y., Huang H., Zhuang Y., Cai T., Wang F., Shao F. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature. 2015;526:660-665.
Not in our library10.1038/nature15514
139.
Schroder K., Tschopp J. The inflammasomes. Cell. 2010;140:821-832.
Not in our library10.1016/j.cell.2010.01.040
140.
Van de Veerdonk F.L., Netea M.G., Dinarello C.A., Joosten L.A. Inflammasome activation and IL-1beta and IL-18 processing during infection. Trends Immunol. 2011;32:110-116.
Not in our library10.1016/j.it.2011.01.003
141.
Man S.M., Karki R., Kanneganti T.D. Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases. Immunol. Rev. 2017;277:61-75.
Not in our library10.1111/imr.12534
142.
New mechanism of nerve injury in Alzheimer’s disease: β‐amyloid‐induced neuronal pyroptosis · 2020
Corrected
143.
Tan M.S., Yu J.T., Jiang T., Zhu X.C., Guan H.S., Tan L. IL12/23 p40 inhibition ameliorates Alzheimer’s disease-associated neuropathology and spatial memory in SAMP8 mice. J. Alzheimers Dis. 2014;38:633-646.
Not in our library10.3233/jad-131148
144.
Halle A., Hornung V., Petzold G.C., Stewart C.R., Monks B.G., Reinheckel T., Fitzgerald K.A., Latz E., Moore K.J., Golenbock D.T. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat. Immunol. 2008;9:857-865.
Not in our library10.1038/ni.1636
145.
Maccioni R.B. Molecular Cytology of Microtubules. 1986;Volume 8:1-124.
Not in our library
146.
Shen H., Han C., Yang Y., Guo L., Sheng Y., Wang J., Li W., Zhai L., Wang G., Guan Q. Pyroptosis executive protein GSDMD as a biomarker for diagnosis and identification of Alzheimer’s disease. Brain Behav. 2021;11:e02063.
Not in our library10.1002/brb3.2063
147.
Gervais F.G., Xu D., Robertson G.S., Vaillancourt J.P., Zhu Y., Huang J., LeBlanc A., Smith D., Rigby M., Shearman M.S., et al. Involvement of caspases in proteolytic cleavage of Alzheimer’s amyloid-beta precursor protein and amyloidogenic A beta peptide formation. Cell. 1999;97:395-406.
Not in our library10.1016/s0092-8674(00)80748-5
148.
Albrecht S., Bourdeau M., Bennett D., Mufson E.J., Bhattacharjee M., LeBlanc A.C. Activation of caspase-6 in aging and mild cognitive impairment. Am. J. Pathol. 2007;170:1200-1209.
Not in our library10.2353/ajpath.2007.060974
149.
Ramcharitar J., Albrecht S., Afonso V.M., Kaushal V., Bennett D.A., Leblanc A.C. Cerebrospinal fluid tau cleaved by caspase-6 reflects brain levels and cognition in aging and Alzheimer disease. J. Neuropathol. Exp. Neurol. 2013;72:824-832.
Not in our library10.1097/nen.0b013e3182a0a39f
150.
Zhang X., Zhu C., Beecham G., Vardarajan B.N., Ma Y., Lancour D., Farrell J.J., Chung J., Alzheimer’s Disease Sequencing P., Mayeux R., et al. A rare missense variant of CASP7 is associated with familial late-onset Alzheimer’s disease. Alzheimers Dement. 2019;15:441-452.
Not in our library10.1016/j.jalz.2018.10.005
151.
Rohn T.T., Head E., Nesse W.H., Cotman C.W., Cribbs D.H. Activation of caspase-8 in the Alzheimer’s disease brain. Neurobiol. Dis. 2001;8:1006-1016.
Not in our library10.1006/nbdi.2001.0449
152.
Rehker J., Rodhe J., Nesbitt R.R., Boyle E.A., Martin B.K., Lord J., Karaca I., Naj A., Jessen F., Helisalmi S., et al. Caspase-8, association with Alzheimer’s Disease and functional analysis of rare variants. PLoS ONE. 2017;12:e0185777.
Not in our library10.1371/journal.pone.0185777
153.
Rohn T.T., Rissman R.A., Davis M.C., Kim Y.E., Cotman C.W., Head E. Caspase-9 activation and caspase cleavage of tau in the Alzheimer’s disease brain. Neurobiol. Dis. 2002;11:341-354.
Not in our library10.1006/nbdi.2002.0549
154.
Caccamo A., Branca C., Piras I.S., Ferreira E., Huentelman M.J., Liang W.S., Readhead B., Dudley J.T., Spangenberg E.E., Green K.N., et al. Necroptosis activation in Alzheimer’s disease. Nat. Neurosci. 2017;20:1236-1246.
Not in our library10.1038/nn.4608
155.
Kischkel F.C., Hellbardt S., Behrmann I., Germer M., Pawlita M., Krammer P.H., Peter M.E. Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J. 1995;14:5579-5588.
Not in our library10.1002/j.1460-2075.1995.tb00245.x
156.
Chinnaiyan A.M., O’Rourke K., Tewari M., Dixit V.M. FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell. 1995;81:505-512.
Not in our library10.1016/0092-8674(95)90071-3
157.
Slee E.A., Adrain C., Martin S.J. Executioner caspase-3, -6, and -7 perform distinct, non-redundant roles during the demolition phase of apoptosis. J. Biol. Chem. 2001;276:7320-7326.
Not in our library10.1074/jbc.m008363200
158.
Slee E.A., Harte M.T., Kluck R.M., Wolf B.B., Casiano C.A., Newmeyer D.D., Wang H.G., Reed J.C., Nicholson D.W., Alnemri E.S., et al. Ordering the cytochrome c-initiated caspase cascade: Hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner. J. Cell Biol. 1999;144:281-292.
Not in our library10.1083/jcb.144.2.281
159.
Li P., Nijhawan D., Budihardjo I., Srinivasula S.M., Ahmad M., Alnemri E.S., Wang X. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell. 1997;91:479-489.
Not in our library10.1016/s0092-8674(00)80434-1
160.
Zou H., Li Y., Liu X., Wang X. An APAF-1.cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J. Biol. Chem. 1999;274:11549-11556.
Not in our library10.1074/jbc.274.17.11549
161.
Callens M., Kraskovskaya N., Derevtsova K., Annaert W., Bultynck G., Bezprozvanny I., Vervliet T. The role of Bcl-2 proteins in modulating neuronal Ca(2+) signaling in health and in Alzheimer’s disease. Biochim. Biophys. Acta Mol. Cell Res. 2021;1868:118997.
Not in our library10.1016/j.bbamcr.2021.118997
162.
Kudo W., Lee H.P., Smith M.A., Zhu X., Matsuyama S., Lee H.G. Inhibition of Bax protects neuronal cells from oligomeric Abeta neurotoxicity. Cell Death Dis. 2012;3:e309.
Not in our library10.1038/cddis.2012.43
163.
Paradis E., Douillard H., Koutroumanis M., Goodyer C., LeBlanc A. Amyloid beta peptide of Alzheimer’s disease downregulates Bcl-2 and upregulates bax expression in human neurons. J. Neurosci. 1996;16:7533-7539.
Not in our library10.1523/jneurosci.16-23-07533.1996
164.
Drache B., Diehl G.E., Beyreuther K., Perlmutter L.S., Konig G. Bcl-xl-specific antibody labels activated microglia associated with Alzheimer’s disease and other pathological states. J. Neurosci. Res. 1997;47:98-108.
Not in our library10.1002/(sici)1097-4547(19970101)47:1<98::aid-jnr11>3.0.co;2-6
165.
Burguillos M.A., Deierborg T., Kavanagh E., Persson A., Hajji N., Garcia-Quintanilla A., Cano J., Brundin P., Englund E., Venero J.L., et al. Caspase signalling controls microglia activation and neurotoxicity. Nature. 2011;472:319-324.
Not in our library10.1038/nature09788
166.
Fricker M., Vilalta A., Tolkovsky A.M., Brown G.C. Caspase inhibitors protect neurons by enabling selective necroptosis of inflamed microglia. J. Biol. Chem. 2013;288:9145-9152.
Not in our library10.1074/jbc.m112.427880
167.
Stadelmann C., Deckwerth T.L., Srinivasan A., Bancher C., Bruck W., Jellinger K., Lassmann H. Activation of caspase-3 in single neurons and autophagic granules of granulovacuolar degeneration in Alzheimer’s disease. Evidence for apoptotic cell death. Am. J. Pathol. 1999;155:1459-1466.
Not in our library10.1016/s0002-9440(10)65460-0
168.
Su J.H., Zhao M., Anderson A.J., Srinivasan A., Cotman C.W. Activated caspase-3 expression in Alzheimer’s and aged control brain: Correlation with Alzheimer pathology. Brain Res. 2001;898:350-357.
Not in our library10.1016/s0006-8993(01)02018-2
169.
Rohn T.T., Kokoulina P., Eaton C.R., Poon W.W. Caspase activation in transgenic mice with Alzheimer-like pathology: Results from a pilot study utilizing the caspase inhibitor, Q-VD-OPh. Int. J. Clin. Exp. Med. 2009;2:300-308.
Not in our library
170.
Biscaro B., Lindvall O., Tesco G., Ekdahl C.T., Nitsch R.M. Inhibition of microglial activation protects hippocampal neurogenesis and improves cognitive deficits in a transgenic mouse model for Alzheimer’s disease. Neurodegener Dis. 2012;9:187-198.
Not in our library10.1159/000330363
171.
Grootjans S., Vanden Berghe T., Vandenabeele P. Initiation and execution mechanisms of necroptosis: An overview. Cell Death Differ. 2017;24:1184-1195.
Not in our library10.1038/cdd.2017.65
172.
Dondelinger Y., Declercq W., Montessuit S., Roelandt R., Goncalves A., Bruggeman I., Hulpiau P., Weber K., Sehon C.A., Marquis R.W., et al. MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates. Cell Rep. 2014;7:971-981.
Not in our library10.1016/j.celrep.2014.04.026
173.
Wang H., Sun L., Su L., Rizo J., Liu L., Wang L.F., Wang F.S., Wang X. Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol. Cell. 2014;54:133-146.
Not in our library10.1016/j.molcel.2014.03.003
174.
Feng S., Yang Y., Mei Y., Ma L., Zhu D.E., Hoti N., Castanares M., Wu M. Cleavage of RIP3 inactivates its caspase-independent apoptosis pathway by removal of kinase domain. Cell. Signal. 2007;19:2056-2067.
Not in our library10.1016/j.cellsig.2007.05.016
175.
Degterev A., Hitomi J., Germscheid M., Ch’en I.L., Korkina O., Teng X., Abbott D., Cuny G.D., Yuan C., Wagner G., et al. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat. Chem. Biol. 2008;4:313-321.
Not in our library10.1038/nchembio.83
176.
Cho Y.S., Challa S., Moquin D., Genga R., Ray T.D., Guildford M., Chan F.K. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell. 2009;137:1112-1123.
Not in our library10.1016/j.cell.2009.05.037
177.
He S., Wang L., Miao L., Wang T., Du F., Zhao L., Wang X. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell. 2009;137:1100-1111.
Not in our library10.1016/j.cell.2009.05.021
178.
Zhang D.W., Shao J., Lin J., Zhang N., Lu B.J., Lin S.C., Dong M.Q., Han J. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science. 2009;325:332-336.
Not in our library10.1126/science.1172308
179.
Sun L., Wang H., Wang Z., He S., Chen S., Liao D., Wang L., Yan J., Liu W., Lei X., et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell. 2012;148:213-227.
Not in our library10.1016/j.cell.2011.11.031
180.
Zhao J., Jitkaew S., Cai Z., Choksi S., Li Q., Luo J., Liu Z.G. Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis. Proc. Natl. Acad. Sci. USA. 2012;109:5322-5327.
Not in our library10.1073/pnas.1200012109
181.
Ofengeim D., Mazzitelli S., Ito Y., DeWitt J.P., Mifflin L., Zou C., Das S., Adiconis X., Chen H., Zhu H., et al. RIPK1 mediates a disease-associated microglial response in Alzheimer’s disease. Proc. Natl. Acad. Sci. USA. 2017;114:E8788-E8797.
Not in our library10.1073/pnas.1714175114
182.
Chung S.H. Aberrant phosphorylation in the pathogenesis of Alzheimer’s disease. BMB Rep. 2009;42:467-474.
Not in our library10.5483/bmbrep.2009.42.8.467
183.
Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death · 2017
No notice
184.
Wang Y., Gao W., Shi X., Ding J., Liu W., He H., Wang K., Shao F. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature. 2017;547:99-103.
Not in our library10.1038/nature22393
185.
Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation · 2019
No notice
186.
Orning P., Weng D., Starheim K., Ratner D., Best Z., Lee B., Brooks A., Xia S., Wu H., Kelliher M.A., et al. Pathogen blockade of TAK1 triggers caspase-8-dependent cleavage of gasdermin D and cell death. Science. 2018;362:1064-1069.
Not in our library10.1126/science.aau2818
187.
Sarhan J., Liu B.C., Muendlein H.I., Li P., Nilson R., Tang A.Y., Rongvaux A., Bunnell S.C., Shao F., Green D.R., et al. Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during Yersinia infection. Proc. Natl. Acad. Sci. USA. 2018;115:E10888-E10897.
Not in our library10.1073/pnas.1809548115
188.
Pompl P.N., Yemul S., Xiang Z., Ho L., Haroutunian V., Purohit D., Mohs R., Pasinetti G.M. Caspase gene expression in the brain as a function of the clinical progression of Alzheimer disease. Arch. Neurol. 2003;60:369-376.
Not in our library10.1001/archneur.60.3.369
189.
Kesavardhana S., Kanneganti T.D. ZBP1: A STARGᐰTE to decode the biology of Z-nucleic acids in disease. J. Exp. Med. 2020;217.
Not in our library10.1084/jem.20200885
190.
Malireddi R.K.S., Tweedell R.E., Kanneganti T.D. PANoptosis components, regulation, and implications. Aging. 2020;12:11163-11164.
Not in our library10.18632/aging.103528
191.
Place D.E., Lee S., Kanneganti T.D. PANoptosis in microbial infection. Curr. Opin. Microbiol. 2021;59:42-49.
Not in our library10.1016/j.mib.2020.07.012
192.
Dunn N., Mullee M., Perry V.H., Holmes C. Association between dementia and infectious disease: Evidence from a case-control study. Alzheimer Dis. Assoc. Disord. 2005;19:91-94.
Not in our library10.1097/01.wad.0000165511.52746.1f
193.
Coperchini F., Chiovato L., Croce L., Magri F., Rotondi M. The cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system. Cytokine Growth Factor Rev. 2020;53:25-32.
Not in our library10.1016/j.cytogfr.2020.05.003
194.
Serrano-Castro P.J., Estivill-Torrus G., Cabezudo-Garcia P., Reyes-Bueno J.A., Ciano Petersen N., Aguilar-Castillo M.J., Suarez-Perez J., Jimenez-Hernandez M.D., Moya-Molina M.A., Oliver-Martos B., et al. Impact of SARS-CoV-2 infection on neurodegenerative and neuropsychiatric diseases: A delayed pandemic? Neurología. 2020;35:245-251.
Not in our library10.1016/j.nrl.2020.04.002
195.
Karki R., Kanneganti T.D. The ‘cytokine storm’: Molecular mechanisms and therapeutic prospects. Trends Immunol. 2021;42:681-705.
Not in our library10.1016/j.it.2021.06.001
196.
Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer's disease · 2005
No notice
197.
Minter M.R., Taylor J.M., Crack P.J. The contribution of neuroinflammation to amyloid toxicity in Alzheimer’s disease. J. Neurochem. 2016;136:457-474.
Not in our library10.1111/jnc.13411
198.
Hu W.T., Howell J.C., Ozturk T., Gangishetti U., Kollhoff A.L., Hatcher-Martin J.M., Anderson A.M., Tyor W.R. CSF Cytokines in Aging, Multiple Sclerosis, and Dementia. Front. Immunol. 2019;10:480.
Not in our library10.3389/fimmu.2019.00480
199.
Genazzani A.D., Forti G., Guardabasso V., Maggi M., Milloni M., Cianfanelli F., Serio M. Frequency of prolactin pulsatile release in normal men and in agonadal patients is neither coupled to LH release nor influenced by androgen modulation. Clin. Endocrinol. 1992;37:65-71.
Not in our library10.1111/j.1365-2265.1992.tb02285.x
200.
Vom Berg J., Prokop S., Miller K.R., Obst J., Kalin R.E., Lopategui-Cabezas I., Wegner A., Mair F., Schipke C.G., Peters O., et al. Inhibition of IL-12/IL-23 signaling reduces Alzheimer’s disease-like pathology and cognitive decline. Nat. Med. 2012;18:1812-1819.
Not in our library10.1038/nm.2965
201.
Rentzos M., Paraskevas G.P., Kapaki E., Nikolaou C., Zoga M., Rombos A., Tsoutsou A., Vassilopoulos D.D. Interleukin-12 is reduced in cerebrospinal fluid of patients with Alzheimer’s disease and frontotemporal dementia. J. Neurol. Sci. 2006;249:110-114.
Not in our library10.1016/j.jns.2006.05.063
202.
Decourt B., Lahiri D.K., Sabbagh M.N. Targeting Tumor Necrosis Factor Alpha for Alzheimer’s Disease. Curr Alzheimer Res. 2017;14:412-425.
Not in our library10.2174/1567205013666160930110551
203.
Meda L., Cassatella M.A., Szendrei G.I., Otvos L., Baron P., Villalba M., Ferrari D., Rossi F. Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature. 1995;374:647-650.
Not in our library10.1038/374647a0
204.
Tan J., Town T., Paris D., Mori T., Suo Z., Crawford F., Mattson M.P., Flavell R.A., Mullan M. Microglial activation resulting from CD40-CD40L interaction after beta-amyloid stimulation. Science. 1999;286:2352-2355.
Not in our library10.1126/science.286.5448.2352
205.
Tan J., Town T., Crawford F., Mori T., DelleDonne A., Crescentini R., Obregon D., Flavell R.A., Mullan M.J. Role of CD40 ligand in amyloidosis in transgenic Alzheimer’s mice. Nat. Neurosci. 2002;5:1288-1293.
Not in our library10.1038/nn968
206.
Chakrabarty P., Ceballos-Diaz C., Beccard A., Janus C., Dickson D., Golde T.E., Das P. IFN-gamma promotes complement expression and attenuates amyloid plaque deposition in amyloid beta precursor protein transgenic mice. J. Immunol. 2010;184:5333-5343.
Not in our library10.4049/jimmunol.0903382
207.
Lue L.F., Rydel R., Brigham E.F., Yang L.B., Hampel H., Murphy G.M., Brachova L., Yan S.D., Walker D.G., Shen Y., et al. Inflammatory repertoire of Alzheimer’s disease and nondemented elderly microglia in vitro. Glia. 2001;35:72-79.
Not in our library10.1002/glia.1072
208.
Laske C., Stransky E., Hoffmann N., Maetzler W., Straten G., Eschweiler G.W., Leyhe T. Macrophage colony-stimulating factor (M-CSF) in plasma and CSF of patients with mild cognitive impairment and Alzheimer’s disease. Curr. Alzheimer Res. 2010;7:409-414.
Not in our library10.2174/156720510791383813
209.
Hirsch-Reinshagen V., Maia L.F., Burgess B.L., Blain J.F., Naus K.E., McIsaac S.A., Parkinson P.F., Chan J.Y., Tansley G.H., Hayden M.R., et al. The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease. J. Biol. Chem. 2005;280:43243-43256.
Not in our library10.1074/jbc.m508781200
210.
Akama K.T., Van Eldik L.J. Beta-amyloid stimulation of inducible nitric-oxide synthase in astrocytes is interleukin-1beta- and tumor necrosis factor-alpha (TNFalpha)-dependent, and involves a TNFalpha receptor-associated factor- and NFkappaB-inducing kinase-dependent signaling mechanism. J. Biol. Chem. 2000;275:7918-7924.
Not in our library10.1074/jbc.275.11.7918
211.
Shaftel S.S., Carlson T.J., Olschowka J.A., Kyrkanides S., Matousek S.B., O’Banion M.K. Chronic interleukin-1beta expression in mouse brain leads to leukocyte infiltration and neutrophil-independent blood brain barrier permeability without overt neurodegeneration. J. Neurosci. 2007;27:9301-9309.
Not in our library10.1523/jneurosci.1418-07.2007
212.
Ghosh S., Wu M.D., Shaftel S.S., Kyrkanides S., LaFerla F.M., Olschowka J.A., O’Banion M.K. Sustained interleukin-1beta overexpression exacerbates tau pathology despite reduced amyloid burden in an Alzheimer’s mouse model. J. Neurosci. 2013;33:5053-5064.
Not in our library10.1523/jneurosci.4361-12.2013
213.
Tarkowski E., Andreasen N., Tarkowski A., Blennow K. Intrathecal inflammation precedes development of Alzheimer’s disease. J. Neurol. Neurosurg. Psychiatry. 2003;74:1200-1205.
Not in our library10.1136/jnnp.74.9.1200
214.
Toll-like receptor 4-dependent upregulation of cytokines in a transgenic mouse model of Alzheimer's disease · 2008
No notice
215.
Savarin-Vuaillat C., Ransohoff R.M. Chemokines and chemokine receptors in neurological disease: Raise, retain, or reduce? Neurotherapeutics. 2007;4:590-601.
Not in our library10.1016/j.nurt.2007.07.004
216.
Xia M.Q., Qin S.X., Wu L.J., Mackay C.R., Hyman B.T. Immunohistochemical study of the beta-chemokine receptors CCR3 and CCR5 and their ligands in normal and Alzheimer’s disease brains. Am. J. Pathol. 1998;153:31-37.
Not in our library10.1016/s0002-9440(10)65542-3
217.
Ishizuka K., Kimura T., Igata-yi R., Katsuragi S., Takamatsu J., Miyakawa T. Identification of monocyte chemoattractant protein-1 in senile plaques and reactive microglia of Alzheimer’s disease. Psychiatry Clin. Neurosci. 1997;51:135-138.
Not in our library10.1111/j.1440-1819.1997.tb02375.x
218.
Smits H.A., Rijsmus A., van Loon J.H., Wat J.W., Verhoef J., Boven L.A., Nottet H.S. Amyloid-beta-induced chemokine production in primary human macrophages and astrocytes. J. Neuroimmunol. 2002;127:160-168.
Not in our library10.1016/s0165-5728(02)00112-1
219.
Lue L.F., Walker D.G., Rogers J. Modeling microglial activation in Alzheimer’s disease with human postmortem microglial cultures. Neurobiol. Aging. 2001;22:945-956.
Not in our library10.1016/s0197-4580(01)00311-6
220.
Fuhrmann M., Bittner T., Jung C.K., Burgold S., Page R.M., Mitteregger G., Haass C., LaFerla F.M., Kretzschmar H., Herms J. Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer’s disease. Nat. Neurosci. 2010;13:411-413.
Not in our library10.1038/nn.2511
221.
Lee S., Varvel N.H., Konerth M.E., Xu G., Cardona A.E., Ransohoff R.M., Lamb B.T. CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer’s disease mouse models. Am. J. Pathol. 2010;177:2549-2562.
Not in our library10.2353/ajpath.2010.100265
222.
Cho S.H., Sun B., Zhou Y., Kauppinen T.M., Halabisky B., Wes P., Ransohoff R.M., Gan L. CX3CR1 protein signaling modulates microglial activation and protects against plaque-independent cognitive deficits in a mouse model of Alzheimer disease. J. Biol. Chem. 2011;286:32713-32722.
Not in our library10.1074/jbc.m111.254268
223.
Holmes C., Boche D., Wilkinson D., Yadegarfar G., Hopkins V., Bayer A., Jones R.W., Bullock R., Love S., Neal J.W., et al. Long-term effects of Abeta42 immunisation in Alzheimer’s disease: Follow-up of a randomised, placebo-controlled phase I trial. Lancet. 2008;372:216-223.
Not in our library10.1016/s0140-6736(08)61075-2
224.
Rabinovici G.D. Controversy and Progress in Alzheimer’s Disease—FDA Approval of Aducanumab. N. Engl. J. Med. 2021;385:771-774.
Not in our library10.1056/nejmp2111320
225.
Budd-Haeberlein S., Von Hein C., Tian Y., Chalkias S., Muralidharan K.K., Chen T., Wu S., Skordos L., Nisenbaum L., Rajagovindan R., et al. EMERGE and ENGAGE topline results: Two phase 3 studies to evaluate aducanumab in patients with early Alzheimer’s disease. Proceedings of the Advances in Alzheimer’s and Parkinson’s Therapies: An AAT-AD/PD Focus Meeting.
Not in our library
226.
Congdon E.E., Sigurdsson E.M. Tau-targeting therapies for Alzheimer disease. Nat. Rev. Neurol. 2018;14:399-415.
Not in our library10.1038/s41582-018-0013-z
227.
Bittar A., Bhatt N., Kayed R. Advances and considerations in AD tau-targeted immunotherapy. Neurobiol. Dis. 2020;134:104707.
Not in our library10.1016/j.nbd.2019.104707
228.
Kim H.S., Suh Y.H. Minocycline and neurodegenerative diseases. Behav. Brain Res. 2009;196:168-179.
Not in our library10.1016/j.bbr.2008.09.040
229.
Howard R., Zubko O., Gray R., Bradley R., Harper E., Kelly L., Pank L., O’Brien J., Fox C., Tabet N., et al. Minocycline 200 mg or 400 mg versus placebo for mild Alzheimer’s disease: The MADE Phase II, three-arm RCT. Effic. Mech. Eval. 2020;7:1-45.
Not in our library10.3310/eme07020
230.
Mangan M.S.J., Olhava E.J., Roush W.R., Seidel H.M., Glick G.D., Latz E. Targeting the NLRP3 inflammasome in inflammatory diseases. Nat. Rev. Drug Discov. 2018;17:588-606.
Not in our library10.1038/nrd.2018.97
231.
Primiano M.J., Lefker B.A., Bowman M.R., Bree A.G., Hubeau C., Bonin P.D., Mangan M., Dower K., Monks B.G., Cushing L., et al. Efficacy and Pharmacology of the NLRP3 Inflammasome Inhibitor CP-456,773 (CRID3) in Murine Models of Dermal and Pulmonary Inflammation. J. Immunol. 2016;197:2421-2433.
Not in our library10.4049/jimmunol.1600035
232.
Esmaeili M.H., Enayati M., Khabbaz Abkenar F., Ebrahimian F., Salari A.A. Glibenclamide mitigates cognitive impairment and hippocampal neuroinflammation in rats with type 2 diabetes and sporadic Alzheimer-like disease. Behav. Brain Res. 2020;379:112359.
Not in our library10.1016/j.bbr.2019.112359
233.
Caspase-1 inhibition alleviates cognitive impairment and neuropathology in an Alzheimer’s disease mouse model · 2018
No notice
234.
Mandrioli J., D’Amico R., Zucchi E., Gessani A., Fini N., Fasano A., Caponnetto C., Chio A., Dalla Bella E., Lunetta C., et al. Rapamycin treatment for amyotrophic lateral sclerosis: Protocol for a phase II randomized, double-blind, placebo-controlled, multicenter, clinical trial (RAP-ALS trial). Medicine. 2018;97:e11119.
Not in our library10.1097/md.0000000000011119
235.
Wang S., Mustafa M., Yuede C.M., Salazar S.V., Kong P., Long H., Ward M., Siddiqui O., Paul R., Gilfillan S., et al. Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer’s disease model. J. Exp. Med. 2020;217.
Not in our library10.1084/jem.20200785
236.
Brazier D., Perry R., Keane J., Barrett K., Elmaleh D.R. Pharmacokinetics of Cromolyn and Ibuprofen in Healthy Elderly Volunteers. Clin. Drug Investig. 2017;37:1025-1034.
Not in our library10.1007/s40261-017-0549-5
237.
Zhang C., Griciuc A., Hudry E., Wan Y., Quinti L., Ward J., Forte A.M., Shen X., Ran C., Elmaleh D.R., et al. Cromolyn Reduces Levels of the Alzheimer’s Disease-Associated Amyloid beta-Protein by Promoting Microglial Phagocytosis. Sci. Rep. 2018;8:1144.
Not in our library10.1038/s41598-018-19641-2
238.
Blacher E., Dadali T., Bespalko A., Haupenthal V.J., Grimm M.O., Hartmann T., Lund F.E., Stein R., Levy A. Alzheimer’s disease pathology is attenuated in a CD38-deficient mouse model. Ann. Neurol. 2015;78:88-103.
Not in our library10.1002/ana.24425
239.
CD38 in Neurodegeneration and Neuroinflammation · 2020
No notice
240.
Lai J., Mei Z.L., Wang H., Hu M., Long Y., Miao M.X., Li N., Hong H. Montelukast rescues primary neurons against Abeta1-42-induced toxicity through inhibiting CysLT1R-mediated NF-kappaB signaling. Neurochem. Int. 2014;75:26-31.
Not in our library10.1016/j.neuint.2014.05.006
241.
Morin N., Jourdain V.A., Morissette M., Gregoire L., Di Paolo T. Long-term treatment with l-DOPA and an mGlu5 receptor antagonist prevents changes in brain basal ganglia dopamine receptors, their associated signaling proteins and neuropeptides in parkinsonian monkeys. Neuropharmacology. 2014;79:688-706.
Not in our library10.1016/j.neuropharm.2014.01.014
242.
Estus S., Shaw B.C., Devanney N., Katsumata Y., Press E.E., Fardo D.W. Evaluation of CD33 as a genetic risk factor for Alzheimer’s disease. Acta Neuropathol. 2019;138:187-199.
Not in our library10.1007/s00401-019-02000-4
243.
β-Amyloid Clustering around ASC Fibrils Boosts Its Toxicity in Microglia · 2020
No notice
244.
Salter M.W., Stevens B. Microglia emerge as central players in brain disease. Nat. Med. 2017;23:1018-1027.
Not in our library10.1038/nm.4397
245.
Marsh S.E., Abud E.M., Lakatos A., Karimzadeh A., Yeung S.T., Davtyan H., Fote G.M., Lau L., Weinger J.G., Lane T.E., et al. The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function. Proc. Natl. Acad. Sci. USA. 2016;113:E1316-E1325.
Not in our library10.1073/pnas.1525466113
246.
Da Mesquita S., Louveau A., Vaccari A., Smirnov I., Cornelison R.C., Kingsmore K.M., Contarino C., Onengut-Gumuscu S., Farber E., Raper D., et al. Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature. 2018;560:185-191.
Not in our library10.1038/s41586-018-0368-8
247.
Olate-Briones A., Escalona E., Salazar C., Herrada M.J., Liu C., Herrada A.A., Escobedo N. The meningeal lymphatic vasculature in neuroinflammation. FASEB J. 2022;36:e22276.
Not in our library10.1096/fj.202101574rr
248.
Da Mesquita S., Papadopoulos Z., Dykstra T., Brase L., Farias F.G., Wall M., Jiang H., Kodira C.D., de Lima K.A., Herz J., et al. Meningeal lymphatics affect microglia responses and anti-Abeta immunotherapy. Nature. 2021;593:255-260.
Not in our library10.1038/s41586-021-03489-0
249.
Blocking meningeal lymphatic drainage aggravates Parkinson’s disease-like pathology in mice overexpressing mutated α-synuclein · 2019
No notice

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