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Down’s syndrome, neuroinflammation, and Alzheimer neuropathogenesis

Donna M Wilcock, W Sue T Griffin

Journal of Neuroinflammation · 2013 · Review

doi:10.1186/1742-2094-10-84

Abstract

Down syndrome (DS) is the result of triplication of chromosome 21 (trisomy 21) and is the prevailing cause of mental retardation. In addition to the mental deficiencies and physical anomalies noted at birth, triplication of chromosome 21 gene products results in the neuropathological and cognitive changes of Alzheimer's disease (AD). Mapping of the gene that encodes the precursor protein (APP) of the β-amyloid (Aβ) present in the Aβ plaques in both AD and DS to chromosome 21 was strong evidence that this chromosome 21 gene product was a principal neuropathogenic culprit in AD as well as DS. The discovery of neuroinflammatory changes, including dramatic proliferation of activated glia overexpressing a chromosome 2 gene product--the pluripotent immune cytokine interleukin-1 (IL-1)--and a chromosome 21 gene product--S100B--in the brains of fetuses, neonates, and children with DS opened the possibility that early events in Alzheimer pathogenesis were driven by cytokines. The specific chromosome 21 gene products and the complexity of the mechanisms they engender that give rise to the neuroinflammatory responses noted in fetal development of the DS brain and their potential as accelerators of Alzheimer neuropathogenesis in DS are topics of this review, particularly as they relate to development and propagation of neuroinflammation, the consequences of which are recognized clinically and neuropathologically as Alzheimer's disease.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 21, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Down syndrome (DS), trisomy 21, is the most common chromosomal defect, with an incidence in the United States of one per seven-hundred and thirty-three live births with the rate of spontaneous abortions among trisomy 21 fetuses being 7-fold that among non-trisomic fetuses. Not only is trisomy 21 the most frequent cause of mental retardation, due to the extensive number of chromosome 21 genes, there is an extremely high incidence of congenital anomalies such as important cardiac and gastrointestinal malformations in trisomy 21. In the brain, neuritic amyloid-β (Aβ) plaques - a characteristic neuropathological feature of Alzheimer’s disease (AD) - are a virtually certain finding in adults with DS and have been noted in some children with DS. For instance, among 12 children with DS, two (ages 8 and 9 years) had Aβ plaques, and among those between the ages of 35 and 45 years, all had neuritic Aβ plaques and other AD pathologies, such as neurofibrillary tangles and glial activation. Although the prediction of AD neuropathological changes at middle age is reported to be a virtual certainty in those with DS, predictions regarding timing of the onset of dementia are less certain, with estimates of approximately 50 to 70% of individuals with DS developing dementia by age 60 to 70 years.

Identification and characterization of early events that contribute to and or regulate the expression of chromosome 21 gene products that are triplicated in DS is vital if we are to understand the ways in which neurodegenerative cycles and the mechanisms they employ in promotion of the neuropathophysiological progression of sporadic AD and of AD in DS. Three such early events have been reported in DS fetuses and each is related to the others as they induce, and are induced by each other and by cytokines subsequent to neuroinflammatory changes. In particular, these include overexpression of two chromosome 21 gene products - APP and S100B - and the resultant overexpression of the pluripotent neuroinflammatory cytokine IL-1, which is encoded by chromosome 2 genes IL-1A and IL-1B. Complex interactions between APP, glial activation, S100B, and IL-1 include upregulation of the expression of IL-1α and β by both APP and S100B, and induction of both APP and S100B by IL-1β. Such interactions have been shown to be elicited by multiple neural insults, each of which is characterized by gliosis-related neuroinflammation and risk for development of the characteristic neuropathological changes of AD.

It is now more than twenty years since the report of prominent glial activation with excessive expression of inflammatory cytokines such as the chromosome 21 gene product S100B and the chromosome 2 gene product IL-1 in DS fetuses, infants, children, and adults in DS, and in AD. Such glial activation and cytokine overexpression occurs years before the virtually certain appearance at middle age of the Aβ plaques in DS. Accompanying reports demonstrated that IL-1 induces the synthesis of APP in non-neural and neural cells; this IL-1 induction of APP was later verified in neurons in in vitro and in vivo studies that included evidence of IL-1 induction of S100B. As evidence that glial activation and neuronal expression of APP are potentially self-propagating events, IL-1 and S100B both induce microglial and astrocytic activation with overexpression of themselves, as well as of neuronal APP. This idea was supported by reports from Barger and Li et al. of neuronal stress-induced excessive expression of neuronal APP and elevated release of sAPP, which, in turn, activates microglia and induces their overexpression of IL-1β. Taken together, these reports suggest that glial activation and resulting cytokine overexpression contribute to APP overexpression and in so doing may favor the appearance of Aβ plaques in children with DS. In DS, then, it may be sufficient to merely invoke gene load-related upregulation of neuronal APP and astrocytic S100B as seminal events that may drive neuronal stress, glial activation, and DS-related neuropathological changes characteristic of AD.

Experimental evidence supports the idea that excessive levels of cytokines such as IL-1 and S100B are key factors in development of the neuropathological changes of AD. For instance in the presence of excess IL-1, whether in brains of experimental animals or in purified rodent neurons in cultures, APP is overexpressed. It is logical to assume that in situ glial activation with excess IL-1β would favor genesis and progression of Aβ plaque maturation, increases in synthesis and phosphorylation of the MAPK-p38 necessary for production of hyperphosphorylated tau and neurofibrillary tangle formation. Such neuroinflammatory consequences are consistent with the idea that any entity, which acts to precipitate changes that lead to genesis of the same entity, may become a self-propagating cycle and thus has the potential to become chronic. If so, neuropathogenesis is, at least in part, the result of self-propagating cycles. By analogy, without regard to the diversity of the source of neuronal stress, for example, traumatic brain injury, epilepsy, aging, or AIDS, the downstream consequence is increased risk for development of the neuropathological changes of AD marked by increased expression of neuronal APP, activation of glia, and neuroinflammatory cytokine expression. Accordingly, exaggeration of such neuronal-glial interaction due to trisomy 21 would be expected to culminate in neuropathogenic cycles that favor the progression in DS of the neuropathological changes of AD.

The danger of chronic induction of neuroinflammation with its manifestation of glial activation and cytokine overexpression is related to the capacity of proinflammatory cytokines such as IL-1β to self-propagate as they, themselves, activate microglia and astrocytes and further excess expression of IL-1β. In addition to IL-1β induction of the precursors of the principal neuropathological changes in AD, viz., APP for Aβ plaques, S100B for non-sensical growth of dystrophic neurites in plaques, synthesis and activation of MAPK-p38 for hyperphosphorylation of tau, favors formation of neurofibrillary tangles. In addition to favoring formation of these anomalies, IL-1β induces the synthesis and the activity of acetylcholinesterase, thus favoring the breakdown of acetylcholine, an important neurotransmitter in learning and memory, which is known to be decreased in AD. Similarly devastating, excess IL-1β, as observed in DS and AD, is associated in vitro and in vivo with decreases in the expression of synaptophysin, which is a hallmark of the synaptic loss in AD. Such neuropathophysiological changes would be expected to further stress neurons, promote more neuroinflammation, and in this way create a self-propagating cycle of ever increasing neuronal stress, dysfunction, and loss.

Microglia, regarded as the principal cells of the brain’s innate immune system, were first identified as a unique glial cell subtype in the second decade of the twentieth century by Pio del Rio Hortega and were later identified immunohistochemically using macrophage cell surface markers. In the second to the last decade of the century, microglia were shown to be a primary source of the pluripotent immune cytokine IL-1, and this together with the astrocyte-derived neuritogenic cytokine S100B, were held to be responsible for neuroinflammatory responses in very early stages of the development of DS, and by analogy, perhaps in AD. More recently, astrocytes and neurons as well as oligodendrocytes and vascular pericytes have been recognized as participants in cytokine-related neuroinflammatory processes.

In AD, microglia expressing some classic activation markers such as major histocompatibility complex (MHC-II) (associated with antigen presentation), CD68 (a lysosomal protein) and CD36 (a class B scavenger receptor) are highly localized to the area immediately surrounding an amyloid plaque or neurofibrillary tangle. While this led some to hypothesize that microglial activation was contributing to the pathology, others proposed they performed a beneficial function in removing Aβ from the brain. On the one hand, correlation between the overexpression of IL-1α in such plaque-associated microglia with plaque formation and progression from immature deposits to mature senile plaques suggests that microglia contribute to formation and progression of Aβ plaques from deposits to mature senile plaques. Similarly, overexpression of IL-1α in activated microglia adjacent to neurons bearing neurofibrillary tangles, as well as the role of IL-1 in promotion of hyperphosphorylated tau suggests a role for activated glia and excess IL-1 in both the production of tangle substrate and in the progression from paired-helical, filamentous threads to non-neuronal, cell-shaped flames of neurofibrillary tangles.

Chromosome 21 genes and neuroinflammation

Triplication of even a small region (21q22.3) on the short arm of chromosome 21, which is referred to as the critical region (DSCR), is sufficient to result in the DS phenotype, prominently including mental retardation, and growth retardation, as well as muscle, joint, and facial features characteristic of DS. Recognizing the importance of an extra copy of this precise region of chromosome 21 in the pathology of DS does not lessen the potential importance of triplication of those chromosome 21 genes, which are located outside this region, in neuropathogenesis. The APP gene does not map to the critical region of chromosome 21, but more than any other gene on chromosome 21, APP has played a seminal role in our understanding of neuropathological changes in AD and DS, as well as in neurological disorders that give rise to precocious development of AD (for review please see). Steve Barger’s discovery of a role for a secreted fragment of APP, sAPP, in synthesis and release of the pro-neuroinflammatory cytokine IL-1, together with studies demonstrating the importance of IL-1 in promotion of neurodegenerative events, underscores the importance of APP, over and above its importance as the precursor of the Aβ in the senile plaques characteristic of AD and DS.

APP

Although the full significance of triplication of the APP gene in Alzheimer pathogenesis in DS is still under investigation, it is clear that there is a dramatic overexpression of the APP gene product in fetal DS, which is accompanied by a similarly dramatic increase in the levels of IL-1 and S100B, two neuroinflammation-promoting cytokines that are known to induce the overexpression of APP in vitro and in vivo.

Glenner’s report of sequence homology between the Aβ peptide derived from brains of those with AD or with DS was the first evidence linking AD to DS, and the APP gene to chromosome 21. Although the 50% increase in APP expression that would be predicted as a consequence of gene loading (1.5×) in trisomy, may not be sufficient to result in the characteristic pathophysiology of DS, but, together with its induction of IL-1 and the resultant increase in APP, may be responsible, at least in part, for the role of APP gene triplication as a determinant of the age at onset of dementia in DS and in the development of the neuropathological changes of AD in DS. In fact, triplication of the APP gene alone is associated with the development of early onset AD. Findings such as these, together with the prominence of Aβ plaques in Alzheimer neuropathology, led to development of the Amyloid Hypothesis, which has served in many ways to expand our understanding of how APP expression could be related to the development not only the Aβ plaque but to a range of the neuropathological features of AD, including neurofibrillary tangles, glial activation, and overexpression of neuroinflammatory cytokines. However, concentration on Aβ plaques and the Amyloid Hypothesis has to some degree led away from the importance of overexpression of APP, itself, in Alzheimer pathogenesis. For example, neuronal stress imposed by a variety of neurological conditions, which are associated with increased risk for development of AD, results in overexpression of APP, release of sAPP, glial activation, and overexpression of IL-1 for genesis of each of the precursors of the neuropathological changes of AD, implying that overexpression of APP starts a cascade of events that gives rise to Aβ deposition rather than Aβ being seminal in Alzheimer pathogenesis. An interesting case that underscores the importance of APP overexpression in Alzheimer pathogenesis is that of a mildly retarded 78-year-old patient with partial trisomy 21 that did not include the APP gene sequence. This patient, although of extremely advanced age for a person with DS, especially without the characteristic changes of AD, showed no clinical signs of dementia, and magnetic resonance imaging (MRI) 6 months before her death showed only minimal cerebral atrophy and no temporal lobe atrophy.

BACE2

Mapping of the chromosome 21 APP gene, from which is cleaved the Aβ fragment present in plaques in DS and AD, together with the discovery of mutations in chromosome 21 genes that are linked to familial AD and the virtual certain prediction of precocious development of AD present in those with trisomy 21, lent credence to the importance of chromosome 21 genes in the development of AD. This idea was reinforced by the mapping of the β-amyloid cleavage enzyme 2 (BACE2) to the DS critical region of chromosome 21, which in concert with the γ-secretase complex is essential for cleavage of Aβ 40 and 42 from APP. On the other hand, α-secretase, which is not encoded on chromosome 21, plays an important function as it cleaves extracellular APP in the middle of the Aβ portion, preventing release of Aβ, acting as a neuroprotectant, and promoting activation of microglia and induction of synthesis and release of the proinflammatory cytokine IL-1β. If BACE2 induced shedding of IL-1 receptor2 (IL-1R2) acts to avail the brain of decoy receptors for IL-1, the levels of IL-1 may be reduced and therefore neuroinflammation responses in DS and AD dampened.

S100B

This astrocyte-derived cytokine is encoded by a chromosome 21 gene located in the DSCR. It is markedly elevated during normal development and is elevated throughout life in DS. Its properties as a neurite extension factor have been suggested as a contributor to normal growth and maintenance of neurons. In excess, as in DS and AD, S100B is associated with marked nonsensical growth of dystrophic neuronal processes, most notably in the neuritic Aβ plaques diagnostic of AD.

Although S100B is important in development of the central nervous system (CNS) and is protective of neurons from insults and promotes survival following injury, elevated blood levels of S100B serve as a marker indicative of stroke severity, survival, and progression from hemorrhage to acute thrombosis as well as severity of traumatic brain injury. Even seemingly minor head trauma in children and young adults is associated with elevated blood levels of S100B. In addition to increased expression of S100B in activated astrocytes in neurological conditions, systemic diseases such as mild to severe liver disease is characterized by dramatic increases in astrocyte-derived S100B expression, encephalopathy, and cognitive decline.

The role of APP and S100B in promoting neuroinflammation

The dramatic increase in the expression of APP and S100B in DS suggests that (i) some gene product on chromosome 21 is dramatically inducing the APP and S100B synthesis in DS and or (ii) some chromosome 21 gene is indirectly inducing such excessive synthesis, via induction of a gene product on another chromosome, which, in turn, induces excessive expression of APP and S100B. Both of these possibilities have been validated in various cell types, including neuronal cells. For example in the first case, S100B induces the synthesis of neuronal APP mRNA and the production of APP. In the second case, Steve Barger provided the first evidence of a link between neuronal stress, APP expression, and neuroinflammation as he showed that the elevated release of the α-secretase cleaved fragment, sAPPα, which accompanies the stress-induced increases in neuronal expression of APP, activates microglia and induces their expression of IL-1β. Together then it may be concluded that both a chromosome 21 gene product, S100B, and a chromosome 2 gene product, IL-1β, contribute to the elevation of APP expression in trisomy 21 to a much greater extent than that expected from gene loading.

Finding relationships between the overexpression APP, S100B, and IL-1β led to a series of experiments to explore mechanisms by which activation of glia and the resultant excess levels of neural IL-1β and S100B influence the neuropathogenesis of AD, as well as the AD of DS. This may be especially the case as such dramatic overexpression of APP as that in DS would be predicted to promote self-propagating cycles of more and more production and release of neuroinflammatory cytokines IL-1 and S100B and a resultant increase in APP. The neuronal strain of such dramatic induction of APP synthesis, together with challenges imposed by, for example Aβ plaques and or the presence of neuropathological changes such as neurofibrillary tangle formation have been shown to be accompanied by decreases in cellular expression of the total polyadenylated mRNA necessary for translation of the many proteins involved in cell functions.

Other lesser-studied chromosome 21 gene products and their importance in neuroinflammatory processes

Each of the chromosome 21 genes cited below encode (Table 1) gene products that also regulate expression of neuroinflammatory processes, and or are regulated by neuroinflammatory cytokines. Although their influence on neuroinflammation and its relation to neuropathogenesis is less studied than APP and S100B, their importance in such pathways should not be underestimated.

CXADR

The chromosome 21 gene that encodes the receptors for coxsackie virus and adenovirus (CXADR) acts as both a viral receptor and as an adhesion molecule associated with tight junctions. It is highly expressed in brain as well as systemic secretory organs such as the pancreas, testis, and small intestine. In the absence of viral infection CXADR expression is elevated in models of myocardial inflammation. In view of triplication of the CXADR gene in trisomy 21 it will be interesting to discover whether there is a pro-inflammatory role for CXADR in the brain similar to that in the heart. This is particularly interesting as CXADR was recently shown to induce stress-activated MAPK pathways in the heart that result in increased production of IFNγ, IL-12, IL-1β, TNFα, and IL-6 as well as changes in tight junction in cardiac vasculature. Increased neural expression of CXADR and its induction of IL-1β and MAPK could contribute to reported MAPK-p38-dependent hyperphosphorylation of tau and tangle formation.

ADAMTS1 and ADAMTS5

IL-1β induces synthesis of two other chromosome 21 genes that encode two secreted proteinases of the ADAMTS gene family (ADAMTS1 and ADAMTS5) that degrade extracellular matrix proteins. This interaction between IL-1β and these proteinases may explain, at least in part, the dramatic overexpression of ADAMTS1 in DS. Moreover, such excessive expression of these proteinases in DS may contribute to degradation of extracellular matrix proteoglycans such as aggrecan and versican in DS.

TIAM1

The chromosome 21 gene for T-cell lymphoma invasion and metastasis-1 (TIAM1) is a critical regulatory factor in IL-1β-induced synthesis of NADPH oxidase, via induction of guanine nucleotide exchange factor for Rac1 that contributes to the activation of Rac1 for the activation of NADPH oxidase in pancreatic β-cells. By analogy, simultaneous excess expression of TIAM1 and IL-1 in DS brain may contribute to the dramatic oxidative stress in DS brain.

SOD1

Superoxide dismutase 1 (SOD1) is a potent endogenous neural-relevant copper and zinc binding enzyme that is encoded on chromosome 21 and acts as a soluble cytoplasmic and mitochondrial interspace protein that converts superoxide radicals to molecular oxygen and hydrogen peroxide. Although the SOD1 gene is most commonly associated with anterolateral sclerosis (ALS) as mutation in SOD1 are linked with genetic susceptibility to ALS. However, overexpression of non-mutated SOD1 in the absence of a peroxide-detoxifying enzyme in the same cellular compartment promotes oxidative stress, suggesting that the elevation of SOD1 due to trisomy 21, if unmatched by increases in the levels of peroxide-detoxifying enzyme, would be detrimental.

IFNAR1, IFNAR2, and IFNGR2

As the genes encoding the receptors for IFNα1 and 2, and for IFN-γ (IFNAR1, IFNAR2, and IFNGR2) are located on chromosome 21 and are therefore all subject to triplication in trisomy 21. IFNAR1 and IFNAR2 respond to IFNα, β, or γ and, upon ligand binding, activate the signaling pathway for induction of proinflammatory cytokines, including IL-1β, TNFα, and IL-6 expression. IFNGR2 uses the same signaling pathway but uniquely responds to IFNγ. In the trisomy 16 mouse model of DS, both the IFNGR2 and IFNAR2 are triplicated. Studies in these mice, which develop significant pathology in utero and rarely survive to birth, show that treatment of trisomy 16 fetuses with anti-IFN IgG improves the mouse phenotype, suggesting that the triplication of the IFN receptors significantly contributes to the lethal pathology present in these mice. Furthermore, a partial knockout of IFNAR2 and IFNGR2 improves growth and viability of cultured neurons derived from trisomy 16 mouse fetuses. Therefore, the expected hyper-responsiveness to IFN in individuals with DS may contribute to the elevated inflammatory profile in the brain as well as systemically.

RIPK4

Receptor-interacting serine-threonine kinase 4 (RIPK4) is a protein kinase involved in multiple cell signaling pathways. One of these pathways is the signaling pathway for the activation of NFκB, which is important in promoting proinflammatory cytokines such as TNFα. In addition, RIPK4 is involved in the signaling cascade of the TNFα receptor TNFR1. It is important to note that TNFR1 is most heavily implicated in the toxic effects of TNFα, suggesting that overexpression of RIPK4 increases responsiveness of TNFR1 to TNFα, exacerbating the effects of TNFR1.

CBS

The chromosome 21 gene product cystathionine beta synthase (CBS) is a cytosolic enzyme that catalyzes the desulfhydration of cysteine for production of hydrogen sulfide, which is now recognized as an atypical cellular messenger that is important in both normal and abnormal cellular functions. Hydrogen sulfide is a complicated signaling molecule with an apparent bimodal action on inflammation, in that low levels appear to be anti-inflammatory, while high levels appear to exacerbate neuroinflammatory processes (for review please see). Overexpression of CBS in trisomy 21 and its relation to development of AD in DS is, at present, unknown.

PRMT2

The enzyme, protein arginine methyltransferase 2 (PRMT2), facilitates the methylation of arginine necessary for regulation of the JAK/STAT signaling pathway, which leads to elevation of expression of neuroinflammatory cytokines IFNγ, IFNα, and IL-6 and via inhibition of NFκB may promote apoptosis. Importantly, degradation of proteins containing methylated arginine results in the production of asymmetric dimethylarginine (ADMA), inhibition of nitric oxide synthase activity, and decreased levels of nitric oxide (NO). If there is an increase in tissue levels of ADMA in DS brain, as there is in the plasma of DS patients with pulmonary hypertension, brain levels of NO may be decreased, the JAK-STAT pathway increased, and changes occur toward the inflammatory state of microglia.

Summary

The principal conclusion one may draw from information presented here regarding the influence of triplication of chromosome 21 genes on neuropathogenesis and development of the clinical and neuropathological manifestations of AD and AD in DS is that many chromosome 21 genes upregulate classical neural immune responses of activated microglia, which are now classified according to systemic immune macrophage profiles as either classical M1 responses that favor overexpression of pro-inflammatory cytokines, or alternative M2 responses that favor overexpression of anti-inflammatory cytokines. As so many chromosome 21 genes are primarily associated with M1, that is, proinflammatory responses, we propose that M1 is the principle glial activation state that will be observed in the DS brain. This is commonsensical as, for example in experimental conditions, triplication of the major IFN receptor genes IFNAR1, IFNAR2 and IFNGR2 is associated with enhancement of interferon signaling and TIAM1, SOD1, and PRMT2 are associated with increases in oxidative stresses, and S100B induces expression of APP as well as IL-1α and β. Moreover, in brains of fetuses, neonates, children, and adults with DS, astrocytes are activated and express excess levels of S100B adjacent to activated microglia overexpressing IL-1α and neurons overexpressing APP. These findings, together with triplication of the βAPP gene in DS and experimental evidence of neuronal stress-induced increases in βAPP expression and parallel secretion of sAPP for resultant activation of microglia, evidenced by increases in oxidative markers and overexpression and release of IL-1β, suggest that triplication of chromosome 21 genes, perhaps especially βAPP, may account for most of the very early neuroinflammatory and oxidative changes in DS. By analogy, the neuronal stress triggered by the many risk factors that favor development of AD, manifested as neuronal overexpression of APP and release of sAPP, may be prime in inducing the dramatic neuroinflammatory responses that then result in a self-amplifying cycle (Figure 1) of increasing neuropathological changes, including neuronal stress, neuroinflammation, and synthesis of the precursors giving rise to formation of the Aβ plaques and neurofibrillary tangles diagnostic of AD.

Relative to other causative factors in individuals at increased risk for development of AD - the small population of individuals with mutations in Aβ-associated genes - trisomy 21 represents the population (one in every seven-hundred and thirty-three live births) with the highest incidence of AD, suggesting that greater attention should be given to investigating DS pathogenesis as it relates to sporadic AD. Such studies could well be directed toward not only discovery of basic molecular mechanisms driven by chromosome 21 gene products but also toward development of rational therapeutic approaches to treatments that may delay onset or slow the progression of AD, thus preserving cognitive functions not only in DS but also in AD itself.

Abbreviations

Aβ: β-amyloid; AD: Alzheimer's disease; ADMA: Asymmetric dimethylarginine; ALS: Anterolateral sclerosis; APP: Precursor protein of β-amyloid; APP: Precursor protein; BACE2: β-amyloid cleavage enzyme 2; CBS: Cystathionine beta synthase; CNS: Central nervous system; DS: Down’s syndrome; DSCR: Down’s syndrome critical region; IL: Interleukin; IFN: Interferon; IL1-R2: Interleukin 1 receptor 2; IgG: Immunoglobulin; JAK: Janus kinase; JNK: c-Jun N-terminal kinase; MAPK: Mitogen-activated protein kinase; MHC: Major histocompatibility complex; MRI: Magnetic resonance imaging; PRMT2: Protein arginine methyltransferase 2; NAPDH: Nicotinamide adenine dinucleotide phosphate-oxidase; NF-κB: Nuclear factor-kappa B; NO: Nitric oxide; PRMT2: Protein arginine methyltransferase 2; RIPK4: Receptor-interacting serine-threonine kinase 4; SOD1: Superoxide dismutase 1; STAT: Signal transducer and activator of transcription; TIAM1: T-cell lymphoma invasion and metastasis-1 TGF, Transforming growth factor; TNF: Tumor necrosis factor.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

MW and WSTG, contributed equally to the writing of this review. Both authors read and approved the final manuscript.

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    Li Y Wang J Sheng JG Liu L Barger SW Jones RA Van Eldik LJ Mrak RE Griffin WS S100 beta increases levels of beta-amyloid precursor protein and its encoding mRNA in rat neuronal culturesJ Neurochem1998 7114211428

    Not in our library10.1046/j.1471-4159.1998.71041421.x

  28. 28.

    Li Y Liu L Kang J Sheng JG Barger SW Mrak RE Griffin WS Neuronal-glial interactions mediated by interleukin-1 enhance neuronal acetylcholinesterase activity and mRNA expressionJ Neurosci2000 20149155

    Not in our library10.1523/jneurosci.20-01-00149.2000

  29. 29.
    Apolipoprotein E expression is elevated by interleukin 1 and other interleukin 1-induced factors · 2011
    Not checked
  30. 30.

    Sheng JG Mrak RE Griffin WS Neuritic plaque evolution in Alzheimer’s disease is accompanied by transition of activated microglia from primed to enlarged to phagocytic formsActa Neuropathol (Berl)1997 9415

    Not in our library10.1007/s004010050664

  31. 31.

    Li Y Liu L Barger SW Griffin WS Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathwayJ Neurosci2003 2316051611

    Not in our library10.1523/jneurosci.23-05-01605.2003

  32. 32.

    Griffin WS Mrak RE Interleukin-1 in the genesis and progression of and risk for development of neuronal degeneration in Alzheimer’s diseaseJ Leukoc Biol2002 72233238

    Not in our library

  33. 33.

    Griffin WS Sheng JG Gentleman SM Graham DI Mrak RE Roberts GW Microglial interleukin-1 alpha expression in human head injury: correlations with neuronal and neuritic beta-amyloid precursor protein expressionNeurosci Lett1994 176133136

    Not in our library10.1016/0304-3940(94)90066-3

  34. 34.

    Sheng JG Boop FA Mrak RE Griffin WS Increased neuronal beta-amyloid precursor protein expression in human temporal lobe epilepsy: association with interleukin-1 alpha immunoreactivityJ Neurochem1994 6318721879

    Not in our library10.1046/j.1471-4159.1994.63051872.x

  35. 35.

    Griffin WS Yeralan O Sheng JG Boop FA Mrak RE Rovnaghi CR Burnett BA Feoktistova A Van Eldik LJ Overexpression of the neurotrophic cytokine S100 beta in human temporal lobe epilepsyJ Neurochem1995 65228233

    Not in our library10.1046/j.1471-4159.1995.65010228.x

  36. 36.
    Apolipoprotein epsilon 3 alleles are associated with indicators of neuronal resilience · 2012
    Not checked
  37. 37.

    Sheng JG Griffin WS Royston MC Mrak RE Distribution of interleukin-1-immunoreactive microglia in cerebral cortical layers: implications for neuritic plaque formation in Alzheimer’s diseaseNeuropathol Appl Neurobiol1998 24278283

    Not in our library10.1046/j.1365-2990.1998.00122.x

  38. 38.

    Sheng JG Mrak RE Griffin WS Microglial interleukin-1 alpha expression in brain regions in Alzheimer’s disease: correlation with neuritic plaque distributionNeuropathol Appl Neurobiol1995 21290301

    Not in our library10.1111/j.1365-2990.1995.tb01063.x

  39. 39.

    Stanley LC Mrak RE Woody RC Perrot LJ Zhang S Marshak DR Nelson SJ Griffin WS Glial cytokines as neuropathogenic factors in HIV infection: pathogenic similarities to Alzheimer’s diseaseJ Neuropathol Exp Neurol1994 53231238

    Not in our library10.1097/00005072-199405000-00003

  40. 40.

    Barger SW DeWall KM Liu L Mrak RE Griffin WS Relationships between expression of apolipoprotein E and beta-amyloid precursor protein are altered in proximity to Alzheimer beta-amyloid plaques: potential explanations from cell culture studiesJ Neuropathol Exp Neurol2008 67773783

    Not in our library10.1097/nen.0b013e318180ec47

  41. 41.

    Mrak RE Sheng JG Griffin WS Correlation of astrocytic S100 beta expression with dystrophic neurites in amyloid plaques of Alzheimer’s diseaseJ Neuropathol Exp Neurol1996 55273279

    Not in our library10.1097/00005072-199603000-00002

  42. 42.

    Sheng JG Zhu SG Jones RA Griffin WS Mrak RE Interleukin-1 promotes expression and phosphorylation of neurofilament and tau proteins in vivoExp Neurol2000 163388391

    Not in our library10.1006/exnr.2000.7393

  43. 43.

    Sheng JG Jones RA Zhou XQ McGinness JM Van Eldik LJ Mrak RE Griffin WS Interleukin-1 promotion of MAPK-p38 overexpression in experimental animals and in Alzheimer’s disease: potential significance for tau protein phosphorylationNeurochem Int2001 39341348

    Not in our library10.1016/s0197-0186(01)00041-9

  44. 44.

    Levin ED Briggs SJ Christopher NC Auman JT Working memory performance and cholinergic effects in the ventral tegmental area and substantia nigraBrain Res1994 657165170

    Not in our library10.1016/0006-8993(94)90964-4

  45. 45.

    Whitehouse PJ Price DL Struble RG Clark AW Coyle JT Delon MR Alzheimer’s disease and senile dementia: loss of neurons in the basal forebrainScience1982 21512371239

    Not in our library10.1126/science.7058341

  46. 46.

    Whitehouse PJ Martino AM Marcus KA Zweig RM Singer HS Price DL Kellar KJ Reductions in acetylcholine and nicotine binding in several degenerative diseasesArch Neurol1988 45722724

    Not in our library10.1001/archneur.1988.00520310028012

  47. 47.

    Coleman PD Yao PJ Synaptic slaughter in Alzheimer’s diseaseNeurobiol Aging2003 2410231027

    Not in our library10.1016/j.neurobiolaging.2003.09.001

  48. 48.

    Callahan LM Vaules WA Coleman PD Progressive reduction of synaptophysin message in single neurons in Alzheimer diseaseJ Neuropathol Exp Neurol2002 61384395

    Not in our library10.1093/jnen/61.5.384

  49. 49.

    Griffin WS Barger SW Neuroinflammatory cytokines-the common thread in Alzheimer’s pathogenesisUS Neurol2010 621927

    Not in our library

  50. 50.

    Pessac B Godin I Alliot F Microglia: origin and developmentBull Acad Natl Med2001 185337346discussion 346–337

    Not in our library

  51. 51.

    Perry VH Gordon S Macrophages and microglia in the nervous systemTrends Neurosci1988 11273277

    Not in our library10.1016/0166-2236(88)90110-5

  52. 52.

    Ling EA Some aspects of amoeboid microglia in the corpus callosum and neighbouring regions of neonatal ratsJ Anat1976 121Pt 12945

    Not in our library

  53. 53.

    Colton CA Wilcock DM Assessing activation states in microgliaCNS Neurol Disord Drug Targets2010 9174191

    Not in our library10.2174/187152710791012053

  54. 54.

    McGeer PL Itagaki S Tago H McGeer EG Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DRNeurosci Lett1987 79195200

    Not in our library10.1016/0304-3940(87)90696-3

  55. 55.

    Perlmutter LS Scott SA Barron E Chui HC MHC class II-positive microglia in human brain: association with Alzheimer lesionsJ Neurosci Res1992 33549558

    Not in our library10.1002/jnr.490330407

  56. 56.

    Xiang Z Haroutunian V Ho L Purohit D Pasinetti GM Microglia activation in the brain as inflammatory biomarker of Alzheimer’s disease neuropathology and clinical dementiaDis Markers2006 2295102

    Not in our library10.1155/2006/276239

  57. 57.

    Sheng JG Mrak RE Griffin WS Glial-neuronal interactions in Alzheimer disease: progressive association of IL-1alpha + microglia and S100beta + astrocytes with neurofibrillary tangle stagesJ Neuropathol Exp Neurol1997 56285290

    Not in our library10.1097/00005072-199703000-00007

  58. 58.

    Anneren G Edman B Down syndrome–a gene dosage disease caused by trisomy of genes within a small segment of the long arm of chromosome 21, exemplified by the study of effects from the superoxide-dismutase type 1 (SOD-1) geneAPMIS Suppl1993 407179

    Not in our library

  59. 59.

    Rahmani Z Blouin JL Creau-Goldberg N Watkins PC Mattei JF Poissonnier M Prieur M Chettouh Z Nicole A Aurias A Sinet P-M Delabar J-M Critical role of the D21S55 region on chromosome 21 in the pathogenesis of Down syndromeProc Natl Acad Sci USA1989 8659585962

    Not in our library10.1073/pnas.86.15.5958

  60. 60.

    Sinet PM Theophile D Rahmani Z Chettouh Z Blouin JL Prieur M Noel B Delabar JM Mapping of the Down syndrome phenotype on chromosome 21 at the molecular levelBiomed Pharmacother1994 48247252

    Not in our library10.1016/0753-3322(94)90140-6

  61. 61.

    Tanzi RE Gusella JF Watkins PC Bruns GA St George-Hyslop P Van Keuren ML Patterson D Pagan S Kurnit DM Neve RL Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locusScience1987 235880884

    Not in our library10.1126/science.2949367

  62. 62.

    Glenner GG Wong CW Quaranta V Eanes ED The amyloid deposits in Alzheimer’s disease: their nature and pathogenesisAppl Pathol1984 2357369

    Not in our library

  63. 63.

    Glenner GG Wong CW Alzheimer’s disease and Down’s syndrome: sharing of a unique cerebrovascular amyloid fibril proteinBiochem Biophys Res Commun1984 12211311135

    Not in our library10.1016/0006-291x(84)91209-9

  64. 64.

    Margallo-Lana M Morris CM Gibson AM Tan AL Kay DW Tyrer SP Moore BP Ballard CG Influence of the amyloid precursor protein locus on dementia in Down syndromeNeurology2004 6219961998

    Not in our library10.1212/01.wnl.0000129275.13169.be

  65. 65.

    Rumble B Retallack R Hilbich C Simms G Multhaup G Martins R Hockey A Montgomery P Beyreuther K Masters CL Amyloid A4 protein and its precursor in Down’s syndrome and Alzheimer’s diseaseN Engl J Med1989 32014461452

    Not in our library10.1056/nejm198906013202203

  66. 66.

    Sleegers K Brouwers N Gijselinck I Theuns J Goossens D Wauters J Del-Favero J Cruts M van Duijn CM Van Broeckhoven C APP duplication is sufficient to cause early onset Alzheimer’s dementia with cerebral amyloid angiopathyBrain2006 129Pt 1129772983

    Not in our library10.1093/brain/awl203

  67. 67.

    Rovelet-Lecrux A Hannequin D Raux G Le Meur N Laquerriere A Vital A Dumanchin C Feuillette S Brice A Vercelletto M Dubas F Frebourg T APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathyNat Genet2006 382426

    Not in our library10.1038/ng1718

  68. 68.

    Hardy JA Higgins GA Alzheimer’s disease: the amyloid cascade hypothesisScience1992 256184185

    Not in our library10.1126/science.1566067

  69. 69.

    Prasher VP Farrer MJ Kessling AM Fisher EM West RJ Barber PC Butler AC Molecular mapping of Alzheimer-type dementia in Down’s syndromeAnn Neurol1998 43380383

    Not in our library10.1002/ana.410430316

  70. 70.

    Lott IT Neurological phenotypes for Down syndrome across the life spanProg Brain Res2012 197101121

    Not in our library10.1016/b978-0-444-54299-1.00006-6

  71. 71.

    St George-Hyslop PH Tanzi RE Polinsky RJ Haines JL Nee L Watkins P Myers RH Feldman RG Pollen D Drachman D Growden J Bruni A Foncin JF Salmon D Frommelt P Amaducci L Sorbi S Piacentini S Stewart GD Hobbs WJ Conneally PM Gusella JF The genetic defect causing familial Alzheimer’s disease maps on chromosome 21Science1987 235885890

    Not in our library10.1126/science.2880399

  72. 72.

    Acquati F Accarino M Nucci C Fumagalli P Jovine L Ottolenghi S Taramelli R The gene encoding DRAP (BACE2), a glycosylated transmembrane protein of the aspartic protease family, maps to the down critical regionFEBS Lett2000 4685964

    Not in our library10.1016/s0014-5793(00)01192-3

  73. 73.

    Zhou S Zhou H Walian PJ Jap BK CD147 is a regulatory subunit of the gamma-secretase complex in Alzheimer’s disease amyloid beta-peptide productionProc Natl Acad Sci U S A2005 10274997504

    Not in our library10.1073/pnas.0502768102

  74. 74.

    Cheon MS Dierssen M Kim SH Lubec G Protein expression of BACE1, BACE2 and APP in Down syndrome brainsAmino Acids2008 35339343

    Not in our library10.1007/s00726-007-0618-9

  75. 75.

    Anderson JP Chen Y Kim KS Robakis NK An alternative secretase cleavage produces soluble Alzheimer amyloid precursor protein containing a potentially amyloidogenic sequenceJ Neurochem1992 5923282331

    Not in our library10.1111/j.1471-4159.1992.tb10128.x

  76. 76.

    Lannfelt L Basun H Wahlund LO Rowe BA Wagner SL Decreased alpha-secretase-cleaved amyloid precursor protein as a diagnostic marker for Alzheimer’s diseaseNat Med1995 1829832

    Not in our library10.1038/nm0895-829

  77. 77.

    Gandy S Greengard P Regulated cleavage of the Alzheimer amyloid precursor protein: molecular and cellular basisBiochimie1994 76300303

    Not in our library10.1016/0300-9084(94)90162-7

  78. 78.

    Barger SW Mattson MP Participation of gene expression in the protection against amyloid beta-peptide toxicity by the beta-amyloid precursor proteinAnn NY Acad Sci1996 777303309

    Not in our library10.1111/j.1749-6632.1996.tb34437.x

  79. 79.

    Kuhn PH Marjaux E Imhof A De Strooper B Haass C Lichtenthaler SF Regulated intramembrane proteolysis of the interleukin-1 receptor II by alpha-, beta-, and gamma-secretaseJ Biol Chem2007 2821198211995

    Not in our library10.1074/jbc.m700356200

  80. 80.

    Allore RJ Friend WC O’Hanlon D Neilson KM Baumal R Dunn RJ Marks A Cloning and expression of the human S100 beta geneJ Biol Chem1990 2651553715543

    Not in our library

  81. 81.

    Haglid KG Hansson HA Ronnback L S-100 in the central nervous system of rat, rabbit and guinea pig during postnatal developmentBrain Res1977 123331345

    Not in our library10.1016/0006-8993(77)90484-x

  82. 82.

    Donato R Cannon BR Sorci G Riuzzi F Hsu K Weber DJ Geczy CL Functions of S100 proteinsCurr Mol Med2013 132457

    Not in our library10.2174/156652413804486214

  83. 83.

    Kligman D Marshak DR Purification and characterization of a neurite extension factor from bovine brainProc Natl Acad Sci USA1985 8271367139

    Not in our library10.1073/pnas.82.20.7136

  84. 84.

    Barger SW Van Eldik LJ Mattson MP S100 beta protects hippocampal neurons from damage induced by glucose deprivationBrain Res1995 677167170

    Not in our library10.1016/0006-8993(95)00160-r

  85. 85.

    Marshak DR S100 beta as a neurotrophic factorProg Brain Res1990 86169181

    Not in our library

  86. 86.

    Reeves RH Yao J Crowley MR Buck S Zhang X Yarowsky P Gearhart JD Hilt DC Astrocytosis and axonal proliferation in the hippocampus of S100b transgenic miceProc Natl Acad Sci USA1994 9153595363

    Not in our library10.1073/pnas.91.12.5359

  87. 87.

    Marshak DR Pesce SA Stanley LC Griffin WS Increased S100 beta neurotrophic activity in Alzheimer’s disease temporal lobeNeurobiol Aging1992 1317

    Not in our library10.1016/0197-4580(92)90002-f

  88. 88.

    Mrak RE Griffin WS The role of activated astrocytes and of the neurotrophic cytokine S100B in the pathogenesis of Alzheimer’s diseaseNeurobiol Aging2001 22915922

    Not in our library10.1016/s0197-4580(01)00293-7

  89. 89.

    Azmitia EC Griffin WS Marshak DR Van Eldik LJ Whitaker-Azmitia PM S100 beta and serotonin: a possible astrocytic-neuronal link to neuropathology of Alzheimer’s diseaseProg Brain Res1992 94459473

    Not in our library

  90. 90.

    Foerch C Otto B Singer OC Neumann-Haefelin T Yan B Berkefeld J Steinmetz H Sitzer M Serum S100B predicts a malignant course of infarction in patients with acute middle cerebral artery occlusionStroke2004 3521602164

    Not in our library10.1161/01.str.0000138730.03264.ac

  91. 91.

    Foerch C Singer OC Neumann-Haefelin T du Mesnil de Rochemont R Steinmetz H Sitzer M Evaluation of serum S100B as a surrogate marker for long-term outcome and infarct volume in acute middle cerebral artery infarctionArch Neurol2005 6211301134

    Not in our library10.1001/archneur.62.7.1130

  92. 92.

    Foerch C Wunderlich MT Dvorak F Humpich M Kahles T Goertler M Alvarez-Sabin J Wallesch CW Molina CA Steinmetz H Sitzer M Montaner J Elevated serum S100B levels indicate a higher risk of hemorrhagic transformation after thrombolytic therapy in acute strokeStroke2007 3824912495

    Not in our library10.1161/strokeaha.106.480111

  93. 93.

    Stein DM Lindell AL Murdock KR Kufera JA Menaker J Bochicchio GV Aarabi B Scalea TM Use of serum biomarkers to predict cerebral hypoxia after severe traumatic brain injuryJ Neurotrauma2012 2911401149

    Not in our library10.1089/neu.2011.2149

  94. 94.
    CSF-Biomarkers in Olympic Boxing: Diagnosis and Effects of Repetitive Head Trauma · 2012
    No notice
  95. 95.

    Tavarez MM Atabaki SM Teach SJ Acute evaluation of pediatric patients with minor traumatic brain injuryCurr Opin Pediatr2012 24307313

    Not in our library10.1097/mop.0b013e3283531ce6

  96. 96.

    Strauss GI Christiansen M Moller K Clemmesen JO Larsen FS Knudsen GM S-100b and neuron-specific enolase in patients with fulminant hepatic failureLiver Transpl2001 7964970

    Not in our library10.1053/jlts.2001.28742

  97. 97.

    Kimura T Budka H Glial fibrillary acidic protein and S-100 protein in human hepatic encephalopathy: immunocytochemical demonstration of dissociation of two glia-associated proteinsActa Neuropathol1986 701721

    Not in our library10.1007/bf00689509

  98. 98.

    Mrak RE Griffin WS Trisomy 21 and the brainJ Neuropathol Exp Neurol2004 63679685

    Not in our library10.1093/jnen/63.7.679

  99. 99.

    Schmechel DE Goldgaber D Burkhart DS Gilbert JR Gajdusek DC Roses AD Cellular localization of messenger RNA encoding amyloid-beta-protein in normal tissue and in Alzheimer diseaseAlzheimer Dis Assoc Disord1988 296111

    Not in our library10.1097/00002093-198802020-00002

  100. 100.

    Griffin WS Ling C White CL III Morrison-Bogorad M Polyadenylated messenger RNA in paired helical filament-immunoreactive neurons in Alzheimer diseaseAlzheimer Dis Assoc Disord1990 46978

    Not in our library

  101. 101.

    Yuen S Smith J Caruso L Balan M Opavsky MA The coxsackie-adenovirus receptor induces an inflammatory cardiomyopathy independent of viral infectionJ Mol Cell Cardiol2011 50826840

    Not in our library10.1016/j.yjmcc.2011.02.011

  102. 102.

    Kuno K Kanada N Nakashima E Fujiki F Ichimura F Matsushima K Molecular cloning of a gene encoding a new type of metalloproteinase-disintegrin family protein with thrombospondin motifs as an inflammation associated geneJ Biol Chem1997 272556562

    Not in our library10.1074/jbc.272.1.556

  103. 103.

    Yamanishi Y Boyle DL Clark M Maki RA Tortorella MD Arner EC Firestein GS Expression and regulation of aggrecanase in arthritis: the role of TGF-betaJ Immunol2002 16814051412

    Not in our library10.4049/jimmunol.168.3.1405

  104. 104.

    Subasinghe W Syed I Kowluru A Phagocyte-like NADPH oxidase promotes cytokine-induced mitochondrial dysfunction in pancreatic beta-cells: evidence for regulation by Rac1Am J Physiol Regul Integr Comp Physiol2011 300R12R20

    Not in our library10.1152/ajpregu.00421.2010

  105. 105.

    Danciger E Dafni N Bernstein Y Laver-Rudich Z Neer A Groner Y Human Cu/Zn superoxide dismutase gene family: molecular structure and characterization of four Cu/Zn superoxide dismutase-related pseudogenesProc Natl Acad Sci USA1986 8336193623

    Not in our library10.1073/pnas.83.11.3619

  106. 106.

    Kim SH Cohen B Novick D Rubinstein M Mammalian type I interferon receptors consists of two subunits: IFNaR1 and IFNaR2Gene1997 196279286

    Not in our library10.1016/s0378-1119(97)00240-0

  107. 107.

    Boselli D Ragimbeau J Orlando L Cappello P Capello M Ambrogio C Chiarle R Marsili G Battistini A Giovarelli M Pellegrini S Novelli F Expression of IFNgammaR2 mutated in a dileucine internalization motif reinstates IFNgamma signaling and apoptosis in human T lymphocytesImmunol Lett2010 1341725

    Not in our library10.1016/j.imlet.2010.08.005

  108. 108.

    Rountree RB Willis CR Dinh H Blumberg H Bailey K Dean C Jr Peschon JJ Holland PM RIP4 regulates epidermal differentiation and cutaneous inflammationJ Invest Dermatol2010 130102112

    Not in our library10.1038/jid.2009.223

  109. 109.

    Sen U Givvimani S Abe OA Lederer ED Tyagi SC Cystathionine beta-synthase and cystathionine gamma-lyase double gene transfer ameliorate homocysteine-mediated mesangial inflammation through hydrogen sulfide generationAm J Physiol Cell Physiol2011 300C155C163

    Not in our library10.1152/ajpcell.00143.2010

  110. 110.

    Ganesh L Yoshimoto T Moorthy NC Akahata W Boehm M Nabel EG Nabel GJ Protein methyltransferase 2 inhibits NF-kappaB function and promotes apoptosisMol Cell Biol2006 2638643874

    Not in our library10.1128/mcb.26.10.3864-3874.2006

  111. 111.
    HCAR and MCAR: The human and mouse cellular receptors for subgroup C adenoviruses and group B coxsackieviruses · 1997
    Not checked
  112. 112.

    Ito M Kodama M Masuko M Yamaura M Fuse K Uesugi Y Hirono S Okura Y Kato K Hotta Y Honda T Kuwano R Aizawa Y Expression of coxsackievirus and adenovirus receptor in hearts of rats with experimental autoimmune myocarditisCirc Res2000 86275280

    Not in our library10.1161/01.res.86.3.275

  113. 113.

    Zen K Liu Y McCall IC Wu T Lee W Babbin BA Nusrat A Parkos CA Neutrophil migration across tight junctions is mediated by adhesive interactions between epithelial coxsackie and adenovirus receptor and a junctional adhesion molecule-like protein on neutrophilsMol Biol Cell2005 1626942703

    Not in our library10.1091/mbc.e05-01-0036

  114. 114.

    Wei P Zhao YG Zhuang L Hurst DR Ruben S Sang QX Protein engineering and properties of human metalloproteinase and thrombospondin 1Biochem Biophys Res Commun2002 293478488

    Not in our library10.1016/s0006-291x(02)00255-3

  115. 115.

    Miguel RF Pollak A Lubec G Metalloproteinase ADAMTS-1 but not ADAMTS-5 is manifold overexpressed in neurodegenerative disorders as down syndrome, Alzheimer’s and Pick’s diseaseBrain Res Mol Brain Res2005 13315

    Not in our library10.1016/j.molbrainres.2004.09.008

  116. 116.

    Kuno K Okada Y Kawashima H Nakamura H Miyasaka M Ohno H Matsushima K ADAMTS-1 cleaves a cartilage proteoglycan, aggrecanFEBS Lett2000 478241245

    Not in our library10.1016/s0014-5793(00)01854-8

  117. 117.

    Tortorella MD Liu RQ Burn T Newton RC Arner E Characterization of human aggrecanase 2 (ADAM-TS5): substrate specificity studies and comparison with aggrecanase 1 (ADAM-TS4)Matrix Biol2002 21499511

    Not in our library10.1016/s0945-053x(02)00069-0

  118. 118.

    Veluthakal R Palanivel R Zhao Y McDonald P Gruber S Kowluru A Ceramide induces mitochondrial abnormalities in insulin-secreting INS-1 cells: potential mechanisms underlying ceramide-mediated metabolic dysfunction of the beta cellApoptosis2005 10841850

    Not in our library10.1007/s10495-005-0431-4

  119. 119.

    Hordijk PL Regulation of NADPH oxidases: the role of Rac proteinsCirc Res2006 98453462

    Not in our library10.1161/01.res.0000204727.46710.5e

  120. 120.

    Cheon MS Kim SH Yaspo ML Blasi F Aoki Y Melen K Lubec G Protein levels of genes encoded on chromosome 21 in fetal Down syndrome brain: challenging the gene dosage effect hypothesis (Part I)Amino Acids2003 24111117

    Not in our library10.1007/s00726-002-0336-2

  121. 121.

    Lott IT Head E Doran E Busciglio J Beta-amyloid, oxidative stress and down syndromeCurr Alzheimer Res2006 3521528

    Not in our library10.2174/156720506779025305

  122. 122.

    Rakhit R Chakrabartty A Structure, folding, and misfolding of Cu, Zn superoxide dismutase in amyotrophic lateral sclerosisBiochim Biophys Acta2006 176210251037

    Not in our library10.1016/j.bbadis.2006.05.004

  123. 123.

    Rosen DR Siddique T Patterson D Figlewicz DA Sapp P Hentati A Donaldson D Goto J O’Regan JP Deng HX Rahmani Z Krizus A McKenna-Yasek D Cayabyab A Gaston SM Berger R Tanzi RE Halperin JJ Herzfeldt B Van den Bergh R Hung W-Y Bird T Deng G Mulder DW Smyth C Laing NG Soriano E Pericak–Vance MA Haines J Rouleau GA Gusella JS Horvitz RH Brown RH Jr Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosisNature1993 3625962

    Not in our library10.1038/362059a0

  124. 124.

    Reaume AG Elliott JL Hoffman EK Kowall NW Ferrante RJ Siwek DF Wilcox HM Flood DG Beal MF Brown RH Jr Scott RW Snider WD Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injuryNat Genet1996 134347

    Not in our library10.1038/ng0596-43

  125. 125.

    Usui S Oveson BC Iwase T Lu L Lee SY Jo YJ Wu Z Choi EY Samulski RJ Campochiaro PA Overexpression of SOD in retina: need for increase in H(2)O(2)-detoxifying enzyme in same cellular compartmentFree Radic Biol Med2011 5113471354

    Not in our library10.1016/j.freeradbiomed.2011.06.010

  126. 126.

    Cenini G Dowling AL Beckett TL Barone E Mancuso C Murphy MP Levine H III Lott IT Schmitt FA Butterfield DA Head E Association between frontal cortex oxidative damage and beta-amyloid as a function of age in Down syndromeBiochim Biophys Acta1822 2012130138

    Not in our library10.1016/j.bbadis.2011.10.001

  127. 127.

    Park JI Strock CJ Ball DW Nelkin BD Interleukin-1beta can mediate growth arrest and differentiation via the leukemia inhibitory factor/JAK/STAT pathway in medullary thyroid carcinoma cellsCytokine2005 29125134

    Not in our library10.1016/j.cyto.2004.10.005

  128. 128.

    Maroun LE Anti-interferon immunoglobulins can improve the trisomy 16 mouse phenotypeTeratology1995 51329335

    Not in our library10.1002/tera.1420510509

  129. 129.

    Maroun LE Heffernan TN Hallam DM Partial IFN-alpha/beta and IFN-gamma receptor knockout trisomy 16 mouse fetuses show improved growth and cultured neuron viabilityJ Interf Cytok Res2000 20197203

    Not in our library10.1089/107999000312612

  130. 130.

    Meylan E Martinon F Thome M Gschwendt M Tschopp J RIP4 (DIK/PKK), a novel member of the RIP kinase family, activates NF-kappa B and is processed during apoptosisEMBO Rep2002 312011208

    Not in our library10.1093/embo-reports/kvf236

  131. 131.

    Dalal NV Pranski EL Tansey MG Lah JJ Levey AI Betarbet RS RNF11 modulates microglia activation through NF-kappaB signalling cascadeNeurosci Lett2012 528174179

    Not in our library10.1016/j.neulet.2012.08.060

  132. 132.

    Albensi BC Mattson MP Evidence for the involvement of TNF and NF-kappaB in hippocampal synaptic plasticitySynapse2000 35151159

    Not in our library10.1002/(sici)1098-2396(200002)35:2<151::aid-syn8>3.0.co;2-p

  133. 133.

    Baranano DE Ferris CD Snyder SH Atypical neural messengersTrends Neurosci2001 2499106

    Not in our library10.1016/s0166-2236(00)01716-1

  134. 134.

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