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The Toxicity and Polymorphism of β-Amyloid Oligomers

Ya-ru Huang, Rui-tian Liu

International Journal of Molecular Sciences · 2020 · Review · CC BY

doi:10.3390/ijms21124477

Abstract

It is widely accepted that β-amyloid oligomers (Aβos) play a key role in the progression of Alzheimer’s disease (AD) by inducing neuron damage and cognitive impairment, but Aβos are highly heterogeneous in their size, structure and cytotoxicity, making the corresponding studies tough to carry out. Nevertheless, a number of studies have recently made remarkable progress in the describing the characteristics and pathogenicity of Aβos. We here review the mechanisms by which Aβos exert their neuropathogenesis for AD progression, including receptor binding, cell membrane destruction, mitochondrial damage, Ca2+ homeostasis dysregulation and tau pathological induction. We also summarize the characteristics and pathogenicity such as the size, morphology and cytotoxicity of dimers, trimers, Aβ*56 and spherical oligomers, and suggest that Aβos may play a different role at different phases of AD pathogenesis, resulting in differential consequences on neuronal synaptotoxicity and survival. It is warranted to investigate the temporal sequence of Aβos in AD human brain and examine the relationship between different Aβos and cognitive impairment.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 26, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

Alzheimer disease (AD) is a chronic neurodegenerative disease which imposes a heavy burden on families and society. The neuropathological profiles of AD are mainly manifested as the extracellular senile plaques aggregated by β-amyloid (Aβ), and the formation of intracellular neurofibrillary tangles aggregated by hyperphosphorylated tau protein. Aβ has normal physiological function and maintains a low concentration in vivo, however, factors such as aging, oxidative stress and gene mutation cause the disruption of Aβ homeostasis, resulting in Aβ accumulation and aggregation, formation of oligomers and fibers, and plaque deposits in brains. Heavy evidence has confirmed that Aβ oligomers (Aβos) are the most neurotoxic aggregates and play a critical role in the occurrence and development of AD by causing functional neuron death, cognitive damage, and dementia. In recent years, Aβos have been extracted and characterized by various methods, and remarkable progress has been made in the mechanism of pathogenesis. In this review, we introduce the neurotoxic mechanisms of Aβos, and review the properties of Aβos with different size, conformation and neurotoxicity.

2. The Formation of Aβos

Aβ is produced principally in neuronal endosomes by hydrolysis of amyloid precursor protein (APP) with β-secretase and γ-secretase, and its release is modulated by synaptic activity. Studies identified that under normal physiological conditions, Aβ can inhibit the excessive activation of synapses and reduce the production of synaptic excitotoxicity. Moreover, Aβ may be an antibacterial peptide in CNS innate immunity, which protects the body from infections, and Aβ aggregation may be a protective response against infection. But under the pathological condition, the production of Aβ increases or the clearance is inhibited, leading to Aβ abnormal accumulation and aggregation to form β-sheet-rich conformations.

Oligomers are soluble polymers assembled by monomers, some of which are intermediates in fibril generation. Oligomers have different molecular weights and conformations, which results in various oligomeric properties. There is plenty of evidence that Aβos contribute to the development of AD, therefore, clarifying the molecular events related to the aggregation of Aβ monomers into toxic Aβos is the key to understand the pathological mechanism of AD. Aβ aggregates can formed by the assembly of two or more monomers through fibril-independent pathway (primary nucleation) or fibril-dependent mechanism (secondary nucleation), in which Aβ monomers aggregate on the surface of fibrils in a prion-like manner. Monitoring the kinetics of Aβ aggregation in vitro with synthetic Aβ, the process is typically divided into three phases: an initial lag phase, a subsequent growth phase and a final stationary phase (Figure 1).

Aβos are intermediates of Aβ aggregation, which are formed in lag phase and growth phase and reveal a range of intermediates with different size, morphology and conformation. Some oligomeric Aβ intermediates such as Aβ dimers, denoted fibrillar oligomers, enter the fibril-forming pathway to form fibrils, whereas others such as Aβ trimers or globulomers pool as stable non-fibrillar oligomers. Latest study showed that non-fibrillar oligomers could convert into fibrillar oligomers but the rate of oligomer conversion was very slow. Aβos were first detected in 1994. Researchers extracted the soluble Aβ component in the brain by a non-denaturing method, and found that Aβ level in the soluble component was related to the severity of AD. The discovery of Aβos and the inconsistency between cognition and brain plaques shifted the focus of Aβ research from fibers to oligomers.

3. The Neurotoxicological Mechanisms of Aβos

The “amyloid cascade hypothesis”, proposed in 1992, suggests that Aβ deposition is the first step in the pathological development of AD, which then leads to tau pathologies, synaptic dysfunction, neuron loss and dementia. Subsequently, due to the significant toxicity of Aβos, and the close relationship between oligomers and cognition and memory, the hypothesis was revised to “Aβos cascade hypothesis”, which suggests that soluble Aβos directly cause neural signal dysfunction, induce neuronal apoptosis, and inhibit synaptic long-term potentiation (LTP). Multiple studies have shown that Aβos exert neurotoxic effects through multiple mechanisms, such as receptor binding, mitochondrial dysfunction, Ca2+ homeostasis dysregulation and tau pathologies (Figure 2).

3.1. Receptor-Mediated Neurotoxicity of Aβos

Aβos can bind to the receptors on the surface of neurons, alter downstream signaling pathways, and cause cell death ultimately. There are more than 20 types of receptors recognized by Aβos such as cellular prion protein (PrPc), glutamate receptors, β2-adrenergic receptor (β2-AR), p75 neurotrophin receptor (p75NTR) and α7-nicotinic acetylcholine receptor (α7nAChR). Under normal physiological conditions, PrPc is an important protein regulating Aβ metabolism in vivo by inhibiting β-secretase activity and decreasing the production of APP intracellular domain (AICD). However, Aβos bind to PrPc and affect PrPc normal physiological functions in AD brains. Aβos can directly interact with PrPc, impair LTP and cause neuritic dystrophy by activating Fyn tyrosine kinase and causing phosphorylation of N-methyl-d-aspartate receptor (NMDAR), but when the expression of PrPc is removed, these adverse effects are deprived.

Aβos can impair the activity of glutamate receptors to interfere with synaptic plasticity. NMDAR is a glutamate receptor, which has ion channel activity, and plays a critical role in regulating synapse formation and synaptic plasticity. Some studies have indicated that Aβos disturbed NMDAR activity and impaired NMDAR-dependent signaling pathway, leading to synaptic loss and the decrease of spinal density. In addition, Aβos disturb the NMDAR-mediated postsynaptic Ca2+ signaling by affecting the function of NMDAR and altering the availability of extracellular glutamate, which causes LTP impairment. α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) is another glutamate receptor containing four subunits GluA1-A4, which participates in modulation of synaptic plasticity and homeostasis. Aβos induce the reduction of AMPAR level by accelerating the degradation, and increase AMPAR ubiquitination, resulting in the loss of AMPAR activity and suppression of synaptic transmission. Moreover, Aβos cause tau hyperphosphorylation and abnormal accumulation in dendritic spines, which in turn deficits the Aβos-mediated AMPAR signaling pathway, forming a vicious cycle.

β2-AR, expressed in hippocampus and cortex, is required for learning and memory. Soluble Aβ42 can bind to the extracellular N terminus of β2-AR and then interfere with AMPAR activity by inducing G-protein/cAMP/protein kinase A (PKA) signaling, which may cause excessive Ca2+ to flow into neurons and induce excitatory neurotoxicity, leading to overactivity of neurons and loss of dendritic spines ultimately. Research has found that low molecular weight (MW) Aβos led to the decrease of β2-AR level and impairment of hippocampal LTP. In addition, β2-AR can promote tau protein phosphorylation through the β2-AR-PKA-JNK signaling pathway. These results demonstrate that β2-AR may have an important effect on AD pathogenesis.

p75NTR is a transmembrane protein, which participates in Aβos-mediated neurodegenerative signals. In cholinergic basal forebrain (cBF) neurons, Aβos bind to cysteine-rich repeat domains 2 and 4, the extracellular domain of p75NTR, to mediate tau pathology, synaptic disorder and promote the degradation of neurons. Removal of p75NTR expression from cBF neurons causes the improvement of Aβ plaque deposition and cognitive impairment and attenuates the tau pathologies in AD transgenic mice. Moreover, after binding to Aβ, p75NTR can regulate Aβ production by interacting with beta-site amyloid precursor protein cleaving enzyme-1 (BACE1) and enhancing the colocalization and internalization of BACE1 and APP, besides, it also has an impact on the clearance and deposition of Aβ. The latest study identified that p75NTR influenced the effect of Aβ42 on the L-type Ca2+ channel current by disturbing the function of voltage-dependent Ca2+ channels, which can be eliminated after decreasing the expression of p75NTR.

Aβos have high affinity with α7nAChR, and lead to the internalization of the Aβ–α7nAChR complex, which induces plaque formation and promotes neurotoxicity. However, some studies have found that α7nAChR had a neuroprotective effect. Activation of α7nAChR inhibited neuronal γ-secretase activity, and p38 or JNK activity, both of which contribute to the alleviation of Aβ burden and Aβ-induced memory deficits.

In addition to the above receptors, Aβos can also bind to paired immunoglobulin-like receptor B (PirB), EphB2 receptor, metabotropic glutamate receptor 5 (mGluR5) and other receptors to exert neurotoxicity. However, it is not explicit that which receptor has the highest affinity to Aβos in brains or induces deadly damage to neurons. Aβos are highly heterogeneous with multiple sizes and conformations, and different oligomers may bind to different receptors. The studies to determine the binding of certain Aβ oligomer to its receptors to exert specific toxicity are warranted.

3.2. Cell Membrane Destruction

Aβos rather than monomers and fibers can directly act on the cell membrane to form channels, and destroy membrane integrity and permeability. High-MW aggregates elevate the intracellular Ca2+ level by increasing the membrane lipid peroxidation reaction and changing the membrane structure and function, resulting in the suppression of LTP and neuronal death. On the other hand, after binding to the β-sheets of the N-terminal residues of Aβos, lipid bilayers stabilize the structure of Aβos and accelerate fiber formation. The molecular docking results showed that the U-shaped oligomers inserted into the membrane and formed ion-permeable pores, which is consistent with the report that Aβ can insert into lipid bilayers and assemble into a β-barrel pore under optimized detergent micelle conditions. Aβos can also interact with lipids and cholesterol in the membrane to exert their toxicity. For example, Aβos strongly bind to GM1 ganglioside located at the external face of the cell membrane to promote LTP impairment, which requires the existence of sialic acid residues of GM1. Moreover, GM1 not only affects Aβos-mediated perforation of cell membrane, but also influences the aggregation and the secondary structure of Aβos. The effect of cholesterol on the toxicity of Aβos to membrane is controversial. Cholesterol can change the structures of Aβos and facilitate the interaction between Aβ and the membrane, on the other hand, cholesterol increases the membrane rigidity and has a protective effect against Aβos-mediated damage.

3.3. Mitochondrial Damage and Ca2+ Homeostasis Dysregulation

Aβos increase Ca2+ influx and cause intracellular Ca2+ homeostasis dysregulation by binding to receptors on neuronal membranes and disrupting the structure and permeability of cell membranes. Increased intracellular Ca2+ induces the activization of the Ca2+/calmodulin-dependent phosphatase calcineurin (CaN) and glycogen synthase kinase 3β (GSK3β), which can induce hyperphosphorylation of tau, impair the transport of brain-derived neurotrophic factor (BDNF) and cause transport dysregulation in both axons and dendrites. Moreover, the destruction of intracellular Ca2+ homeostasis causes mitochondrial Ca2+ overload and mitochondrial dysfunction. The mitochondrial Ca2+ dysregulation then directly induces superoxide generation, ATP utilization and neuron death by increasing the opening of mitochondrial permeability transition pores (MPTP) and activization of Ca2+-dependent proteases (calpains). In addition, Aβos elevate parkin level in mitochondria and induce mitochondrial dysfunction, but these adverse effects are eliminated when parkin is overexpressed. Mitophagy is an essential cell activity to degrade and remove damaged mitochondria or excess mitochondria, which participates in the adjustment of the functional integrity of the mitochondrial network and cell survival. Mitochondrial Ca2+ dysregulation also interferes with mitophagy, which further aggravates the generation of Aβ aggregates and AD pathological development, forming a vicious cycle between Aβos and mitochondrial disability.

3.4. Tau Pathologies

Aβ and tau are two main pathogenic factors in the pathogenesis of AD. Although there is no clear answer which is the key factor responsible for the onset of AD, some progress in our understanding of the relationship between Aβ and tau has been achieved in recent years. Longitudinal evaluations of Aβ and tau PET imaging have indicated that Aβ deposition first appears in the cortex, at least 10–20 years earlier than clinical symptoms, which precedes the development of tau lesions, neuron death and hippocampal volume loss. The rate of Aβ accumulation can predict the occurrence of tau aggregation, and the rate of tau accumulation is associated with decreased global cognition, which can predict the severity of cognitive impairment. Examining the interaction between Aβ and tau indicated that Aβ deposition may be used as seeds to facilitate the pathological development of tau by creating a unique environment, which is coincident with the research that tau aggregates could not widely spread in the absence of Aβ deposition. In addition, Aβos bind to α2AAR receptors on the surface of neurons, thereby activate GSK3β and promote tau hyperphosphorylation. The required concentration of Aβos to promote tau hyperphosphorylation through this pathway is much lower than that to play direct effects. However, latest study showed that tau burden first emerged in entorhinal cortex and hippocampus of AD patients, which preceded the global cortical Aβ by about 3 years.

4. The Polymorphism of Aβos

Aβos are highly heterogeneous and exhibit diversities in size, conformation, aggregation mode, toxicity and appearance time in the brain. In order to accurately explore the characteristics of different Aβos, the first step is to separate oligomers with different sizes or conformations. Currently, some approaches such as centrifugation and size exclusion chromatography (SEC) can separate oligomers according to molecular size but cannot distinguish conformations. Multiple Aβos-specific antibodies such as A11, OC, as well as W20, NAbs-Aβo, prepared in our laboratory, have been confirmed to recognize the advanced conformation of Aβos, which can be used to extract Aβos with different conformations. Separated by these strategies, the properties of different Aβos can be studied detailly. Next, we review the characteristics and toxicity of several main types of oligomers, including dimers, trimers, Aβ*56, and spherical oligomers (Table 1).

4.1. Aβ Dimers

Aβ dimers are the smallest Aβ aggregates, and they have three characteristics: high levels in the brains of AD patients and transgenic mice, stable in SDS and strong denaturants, and significant neurotoxicity. When treated with 6.8M guanidine thiocyanate, the soluble Aβ aggregates and insoluble Aβ plaques in AD brains are dispersed into two bands in SDS gel electrophoresis (SDS-PAGE), such as Aβ monomers and dimers. It is proposed that Aβ dimers are formed by cross-link via tyrosine acid residue phenol coupling (DiY) and enzymatic coupling (QK) between glutamine and tyrosine residues, resulting in the resistance of dimers to the strong denaturants. The latest study showed that Aβ dimers derived from AD human brains were composed of multiple Aβ monomers with different lengths, and these different monomers were covalently coupled at the ASP1 and Glu22 sites to form stable dimers. However, it is unclear whether the toxicities of the dimers formed through different cross-linking sites are different.

It is generally considered that Aβ dimers may be the basic constituent unit of fibers or oligomers. In Tg2576 and J20 model mice, Aβ dimers were detected after the age of 10 months, in which a large number of plaque deposits appeared in the cortex, indicating that there may be some connections between Aβ dimers and fibers. Moreover, Aβ dimers are generally observed in AD patients over 60 years old. The level of Aβ dimers subsequently increases sharply, which shows the positive correlation between dimers and plaque in the brains. In addition, soluble Aβos in the brain extracts of AD patients were broken down into two molecules of 6.1–7.9 kDa and 3.5–4.5 kDa, when treated with strong denaturants. It is thus speculated that Aβ dimers may also be the basic unit of Aβos.

Adding brain-derived Aβ dimers to primary neurons can reduce the length of neurons, trigger synaptic damage and neuron death, inhibit LTP response and induce tau hyperphosphorylation. In tgDimer mouse, Aβ dimers contribute to the reduction of hippocampal acetylcholine and serotonin turnover rates, resulting in neurotransmitter dysfunction and behavioral impairments. The latest study identified that brain-derived Aβ dimers caused neuronal overactivation by inhibiting the glutamate reuptake process. This process occurs earlier than clinical symptoms and plaque formation, indicating that Aβ dimers may contribute to the early development of AD.

4.2. Aβ Trimers

Although there is no obvious correlation between the trimers and plaque deposits, Aβ trimers are considered to be an aggregation unit of multiple Aβos such as hexamers and dodecamers. Studies have shown that Aβ*56 is a type of Aβos assembled by trimers and the first step of amylospheroids (ASPD) formation is to from trimers. Moreover, Aβ trimers are the earliest Aβ aggregates in the brains of AD human and transgenic mice. In the primary cortical neurons of Tg2576 mice, monomers and trimers can be detected before dimers, indicating that trimers may be produced at the early stage. Further research suggested that Aβ trimers first appeared in the embryonic stage of Tg2576 mice, then increased steadily with aging, and existed throughout life. Consistent with AD animal models, in human brain, the trimers exist since childhood, and their levels gradually increase with age, but there is no significant correlation between trimers and plaque deposits.

The toxicity of Aβ trimers is currently controversial. It was found that trimers and tetramers prepared by PICUP aggregation had prominent toxicity to neurons, but the toxicity of dimers was very weak. Moreover, reducing the amount of Aβ trimers in the brain of APP/PS1 mice significantly alleviated the cognitive impairment. When the cultured primary neurons were treated with Aβ trimers isolated from brain tissues of AD patients, trimers induced the change of tau conformation and caused the disruption of axonal transport, both of which were associated with reduction of the kinesin-1 light chain (KLC1). However, some studies argued that Aβ trimers acted only as a fundamental assembly unit for toxic assemblies rather than a toxic element. They found that the trimers isolated from 7PA2 cells or AD mouse brains significantly inhibited the LTP response, but the toxicity was smaller than homodimers and Aβ*56. In addition, there is no clear relationship between Aβ trimers and the cognitive ability of AD mice, and the connection between trimers and hyperphosphorylation of tau protein in the brain of AD patients is also ambiguous.

4.3. Aβ*56

Aβ*56, first detected in Tg2576 mice, is consistent with the occurrence and development trend of cognitive impairment in mice. Some studies have also reported the appearance of Aβ*56 in other AD transgenic mouse models, such as J20 mice, Arc6/48 mice, and 3xTgAD mice. In AD human brains, the level of Aβ*56 is negligible in children and adolescents, but the level rises above baseline and then steadily rises after the age of 40. Aβ*56 can be recognized by oligomer-specific antibody A11, but not by fiber-specific antibody OC, indicating that Aβ*56 is a non-fibrous Aβ aggregate. Moreover, in brains of AD transgenic mice, Aβ*56 mainly locates on the plaque free tissue and halo, but not plaque core, suggesting that it may have a greater effect on cognitive impairment than other Aβos wrapped in the plaque core.

It is generally considered that Aβ*56 has conspicuous toxicity to neurons, and is related to cognitive impairment in a variety of AD transgenic mice. The expression of Aβ*56 in olfactory epithelium significantly increases in the early onset of Tg2576 transgenic mice. Brain-derived Aβ*56 causes memory impairment by injecting to the brains of normal rats. The mechanism by which Aβ*56-induced neurotoxicity is that Aβ*56 mainly binds to NMDAR on neuronal membranes to elevate NMDAR-dependent intracellular Ca2+ concentration by increasing Ca2+ inflow and activate Ca2+-dependent calmodulin kinase IIα (CaMKIIα). The activated CaMKIIα may promote the hyperphosphorylation of tau at Ser202 and Ser416 and trigger AD-related pathological changes. Moreover, a recent study suggested that Aβ*56 also damaged ubiquitin-dependent and ubiquitin-independent proteasome functions and promoted cell death.

4.4.1. ASPD

ASPD are spherical oligomers assembled by Aβ40 or Aβ42 with diameter being ∼11.9 ± 1.7 nm in transmission electron microscopic (TEM) images. ASPD can be assembled into spherical oligomers with a molecular weight of 330 kDa in units of trimers after 5 h of aggregation in vitro. Even if the reaction time exceeds 24 h, the main fragment in the solution remains to be oligomers without fiber formation, indicating that ASPD aggregation is off-fibril pathway. ASPD do not bind to A11 and OC, indicating that they have a unique conformation different from Aβ dimers, Aβ*56 and other A11-reactive entities. Previous study demonstrated that ASPD had higher neurotoxicity by exerting synaptic damage and inhibiting LTP, but ASPD did not exhibit toxicity to glial cells when they were applied to rat hippocampal slices. After binding to the fourth extracellular loop (Ex4) of Na+/K+-ATPase α3 subunit (NAKα3) in neurons, brain-derived ASPD cause the impairment of NAKα3-specific activity and the activation of N-type voltage-gated calcium channels, both of which can increase cytoplasmic Ca2+ levels and induce mitochondrial calcium dyshomeostasis, leading to mature neurons death and cognitive impairment eventually. Further research on the distribution and spread of ASPD among different neurons identified that ASPD mainly accumulated in the trans-Golgi network of excitatory neurons and after secreted by these neurons, ASPD invaded and caused the death of surrounding NAKα3-positive neurons. In general, ASPD are Aβos with unique conformation and robust neurotoxicity.

4.4.2. ADDLs

Aβ-derived diffusible aggregates (ADDLs) are also spherical oligomers that can be detected in AD human brains. The content of ADDLs in brain of Tg2576 mice increases by 5–100 times before a change in spatial memory. ADDLs are small sphere with a diameter of 5–6 nm and can be specifically recognized by the ADDLs-specific antibodies termed as NUx. ADDLs bind to mature neurons, generate neurotoxicity, and induce abnormal autophagy of neurons. In addition, ADDLs can reduce the level of insulin receptor in neurons and disrupt normal insulin signaling. They may also bind to EPhB2, trigger the receptor degradation and the phosphorylation of NMDAR, and impair synaptic plasticity. Moreover, ADDLs can lead to abnormal localization of tau to dendrites of primary neurons by activating tyrosine kinase Fyn. The latest study showed that after binding to the dendrites and spines of cortical pyramidal neurons, ADDLs induced the rapid depletion of kalirin-7 and caused spine dysgenesis.

5. Discussion

It is widely accepted that Aβos rather than monomers and fibrils play a critical role in AD progression. Aβos can trigger a series of toxic reactions in neurons, such as receptor disability, mitochondrial damage, Ca2+ homeostasis dysregulation and abnormal tau phosphorylation, but the abnormalities of these activities also aggravate accumulation and aggregation of Aβ, forming a vicious cycle. In addition, Aβos are unstable and highly heterogeneous, having various sizes, structures and toxicities both in vivo and in vitro, and play different roles at different phages of AD pathogenesis, resulting in differential consequences on neuronal synaptotoxicity and survival.

Because of the important roles of Aβ in AD pathogenicity, many drugs targeting Aβ have been developed to reduce the production of Aβ or promote the removal of Aβ aggregates and plaque deposits in the brain. Unfortunately, these drugs have failed in the clinical trials due to severe side effects or inability to improve cognitive impairment of AD patients. There may be four reasons for the failure of Aβ-targeted treatment strategies. Firstly, a large number of clinical trials have shown that β-secretase and γ-secretase inhibitors not only fail to effectively improve cognitive impairment of AD patients, but also lead to cognitive deterioration and serious side effects, which may be attributable to the sharp decrease in the levels of Aβ monomer and secretases, resulting in the inhibition of normal physiological functions of Aβ monomers and secretases. Secondly, many antibodies and vaccines targeting Aβ monomers, oligomers or fibers, such as bapinezumab, solanezumab and AN-1792 may not effectively bind to pathogenic oligomer, and usually induce serious side effects. Thirdly, the stage is too late for the tested drugs to interfere with AD development. Aβ aggregates exist in the brain as early as 10–20 years before the occurrence of clinical symptoms, but the current clinical trials of drugs intervene on patients with mild-to-moderate symptomatic. At this stage, a large number of neuronal deaths and irreversible cognitive impairments have occurred in the brains of patients. Finally, AD is a chronic neurodegenerative disease with complex pathological mechanisms, and the exact pathogenesis is currently unclear. In addition to the amyloid cascade hypothesis, researchers also found that tau protein, neuroinflammation and other factors also play important roles in the development of AD. According to the current theoretical basis, drugs just against Aβ may not effectively reverse the pathological processes of AD. In the future, the combination of multiple drugs targeting different pathogenic factors should be considered, which may bring exciting results to AD treatment.

Although significant progress in understanding the biological characteristics of Aβ and the role in the pathogenesis of AD have been made, we have not yet clarified the aggregation kinetics of Aβ, and systematically understood the relationship between different Aβos and AD development due to the heterogeneity and instability of Aβos. Some methods used in the current study to extract and detect Aβos, such as denaturants and SDS-PAGE, may affect the structures and properties of Aβos. In order to obtain high-purity and biologically active Aβos, more gentle methods to separate and purify different Aβos should be explored. In recent years, the acquisition of Aβos has been transformed from incubation with synthesized Aβ to extraction from the brains of AD transgenic mice, making it possible to explore the relationship between pathophysiologic Aβos and AD pathological changes. However, the biological characteristics of Aβos in the brain of AD patients are scarcely studied. Moreover, Aβos exist in the brain long before the occurrence of clinical symptoms, and it is necessary to monitor Aβos in the brain of patients at the preclinical stage to clarify the chronological sequence of different Aβos in AD human, and their detailed toxic mechanisms. More importantly, the structural characteristics of Aβos that play a vital role in AD pathology should be analyzed, and then the therapies against these toxic Aβos could be designed and developed.

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    Not in our library10.1016/j.nbd.2008.01.010

  22. 22.

    Tabaton M., Nunzi M.G., Xue R., Usiak M., Autilio-Gambetti L., Gambetti P. Soluble amyloid beta-protein is a marker of Alzheimer amyloid in brain but not in cerebrospinal fluid. Biochem. Biophys. Res. Commun. 1994;200:1598-1603.

    Not in our library10.1006/bbrc.1994.1634

  23. 23.

    Frackowiak J., Zoltowska A., Wisniewski H.M. Non-fibrillar beta-amyloid protein is associated with smooth muscle cells of vessel walls in Alzheimer disease. J. Neuropathol. Exp. Neurol. 1994;53:637-645.

    Not in our library10.1097/00005072-199411000-00011

  24. 24.

    Hardy J.A., Higgins G.A. Alzheimer’s disease: The amyloid cascade hypothesis. Science. 1992;256:184-185.

    Not in our library10.1126/science.1566067

  25. 25.

    Hardy J., Selkoe D.J. The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science. 2002;297:353-356.

    Not in our library10.1126/science.1072994

  26. 26.

    Mroczko B., Groblewska M., Litman-Zawadzka A., Kornhuber J., Lewczuk P. Cellular Receptors of Amyloid beta Oligomers (AbetaOs) in Alzheimer’s Disease. Int J. Mol. Sci. 2018;19:1884.

    Not in our library10.3390/ijms19071884

  27. 27.

    Vincent B., Sunyach C., Orzechowski H.D., St George-Hyslop P., Checler F. p53-Dependent transcriptional control of cellular prion by presenilins. J. Neurosci. 2009;29:6752-6760.

    Not in our library10.1523/jneurosci.0789-09.2009

  28. 28.

    Younan N.D., Chen K.F., Rose R.S., Crowther D.C., Viles J.H. Prion protein stabilizes amyloid-beta (Abeta) oligomers and enhances Abeta neurotoxicity in a Drosophila model of Alzheimer’s disease. J. Biol. Chem. 2018;293:13090-13099.

    Not in our library10.1074/jbc.ra118.003319

  29. 29.

    Pagano K., Galante D., D’Arrigo C., Corsaro A., Nizzari M., Florio T., Molinari H., Tomaselli S., Ragona L. Effects of Prion Protein on Abeta42 and Pyroglutamate-Modified AbetapEpsilon3-42 Oligomerization and Toxicity. Mol. Neurobiol. 2019;56:1957-1971.

    Not in our library10.1007/s12035-018-1202-x

  30. 30.

    Haas L.T., Salazar S.V., Kostylev M.A., Um J.W., Kaufman A.C., Strittmatter S.M. Metabotropic glutamate receptor 5 couples cellular prion protein to intracellular signalling in Alzheimer’s disease. Brain. 2016;139:526-546.

    Not in our library10.1093/brain/awv356

  31. 31.

    Um J.W., Nygaard H.B., Heiss J.K., Kostylev M.A., Stagi M., Vortmeyer A., Wisniewski T., Gunther E.C., Strittmatter S.M. Alzheimer amyloid-beta oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Nat. Neurosci. 2012;15:1227-1235.

    Not in our library10.1038/nn.3178

  32. 32.
    PrP is a central player in toxicity mediated by soluble aggregates of neurodegeneration-causing proteins · 2019
    No notice
  33. 33.

    Zhang D., Qi Y., Klyubin I., Ondrejcak T., Sarell C.J., Cuello A.C., Collinge J., Rowan M.J. Targeting glutamatergic and cellular prion protein mechanisms of amyloid beta-mediated persistent synaptic plasticity disruption: Longitudinal studies. Neuropharmacology. 2017;121:231-246.

    Not in our library10.1016/j.neuropharm.2017.03.036

  34. 34.

    Li F., Tsien J.Z. Memory and the NMDA receptors. N. Engl. J. Med. 2009;361:302-303.

    Not in our library10.1056/nejmcibr0902052

  35. 35.

    Muller M.K., Jacobi E., Sakimura K., Malinow R., von Engelhardt J. NMDA receptors mediate synaptic depression, but not spine loss in the dentate gyrus of adult amyloid Beta (Abeta) overexpressing mice. Acta Neuropathol. Commun. 2018;6:110.

    Not in our library10.1186/s40478-018-0611-4

  36. 36.

    Liang J., Kulasiri D., Samarasinghe S. Computational investigation of Amyloid-beta-induced location- and subunit-specific disturbances of NMDAR at hippocampal dendritic spine in Alzheimer’s disease. PLoS ONE. 2017;12:e0182743.

    Not in our library10.1371/journal.pone.0182743

  37. 37.

    Diering G.H., Huganir R.L. The AMPA Receptor Code of Synaptic Plasticity. Neuron. 2018;100:314-329.

    Not in our library10.1016/j.neuron.2018.10.018

  38. 38.

    Zhang Y., Guo O., Huo Y., Wang G., Man H.Y. Amyloid-beta Induces AMPA Receptor Ubiquitination and Degradation in Primary Neurons and Human Brains of Alzheimer’s Disease. J. Alzheimers Dis. 2018;62:1789-1801.

    Not in our library10.3233/jad-170879

  39. 39.

    Miller E.C., Teravskis P.J., Dummer B.W., Zhao X., Huganir R.L., Liao D. Tau phosphorylation and tau mislocalization mediate soluble Abeta oligomer-induced AMPA glutamate receptor signaling deficits. Eur. J. Neurosci. 2014;39:1214-1224.

    Not in our library10.1111/ejn.12507

  40. 40.

    Wang D., Fu Q., Zhou Y., Xu B., Shi Q., Igwe B., Matt L., Hell J.W., Wisely E.V., Oddo S., et al. Beta2 adrenergic receptor, protein kinase A (PKA) and c-Jun N-terminal kinase (JNK) signaling pathways mediate tau pathology in Alzheimer disease models. J. Biol. Chem. 2013;288:10298-10307.

    Not in our library10.1074/jbc.m112.415141

  41. 41.

    Wang D., Govindaiah G., Liu R., De Arcangelis V., Cox C.L., Xiang Y.K. Binding of amyloid beta peptide to beta2 adrenergic receptor induces PKA-dependent AMPA receptor hyperactivity. FASEB J. 2010;24:3511-3521.

    Not in our library10.1096/fj.10-156661

  42. 42.

    Yang T., Li S., Xu H., Walsh D.M., Selkoe D.J. Large Soluble Oligomers of Amyloid beta-Protein from Alzheimer Brain Are Far Less Neuroactive Than the Smaller Oligomers to Which They Dissociate. J. Neurosci. 2017;37:152-163.

    Not in our library10.1523/jneurosci.1698-16.2016

  43. 43.

    Wang Y.R., Wang J., Liu Y.H., Hu G.L., Gao C.Y., Wang Y.J., Zhou X.F., Zeng F. Cysteine-Rich Repeat Domains 2 and 4 are Amyloid-beta Binding Domains of Neurotrophin Receptor p75NTR and Potential Targets to Block Amyloid-beta Neurotoxicity. J. Alzheimers Dis. 2018;63:139-147.

    Not in our library10.3233/jad-171012

  44. 44.
    Neurotrophin receptor p75 mediates amyloid β-induced tau pathology · 2019
    Not checked
  45. 45.

    Manucat-Tan N.B., Shen L.L., Bobrovskaya L., Al-Hawwas M., Zhou F.H., Wang Y.J., Zhou X.F. Knockout of p75 neurotrophin receptor attenuates the hyperphosphorylation of Tau in pR5 mouse model. Aging Albany Ny. 2019;11:6762-6791.

    Not in our library10.18632/aging.102202

  46. 46.

    Qian L., Milne M.R., Shepheard S., Rogers M.L., Medeiros R., Coulson E.J. Removal of p75 Neurotrophin Receptor Expression from Cholinergic Basal Forebrain Neurons Reduces Amyloid-beta Plaque Deposition and Cognitive Impairment in Aged APP/PS1 Mice. Mol. Neurobiol. 2019;56:4639-4652.

    Not in our library10.1007/s12035-018-1404-2

  47. 47.

    Saadipour K., Manucat-Tan N.B., Lim Y., Keating D.J., Smith K.S., Zhong J.H., Liao H., Bobrovskaya L., Wang Y.J., Chao M.V., et al. p75 neurotrophin receptor interacts with and promotes BACE1 localization in endosomes aggravating amyloidogenesis. J. Neurochem. 2018;144:302-317.

    Not in our library10.1111/jnc.14206

  48. 48.

    Yao X.Q., Jiao S.S., Saadipour K., Zeng F., Wang Q.H., Zhu C., Shen L.L., Zeng G.H., Liang C.R., Wang J., et al. p75NTR ectodomain is a physiological neuroprotective molecule against amyloid-beta toxicity in the brain of Alzheimer’s disease. Mol. Psychiatry. 2015;20:1301-1310.

    Not in our library10.1038/mp.2015.49

  49. 49.

    Wang Y., Tang H., Yang C., Zhao H., Jian C. Involvement of p75NTR in the effects of Abeta on L-type Ca(2+) channel in cultured neuronal networks. Life Sci. 2020;243:117293.

    Not in our library10.1016/j.lfs.2020.117293

  50. 50.

    Cecon E., Dam J., Luka M., Gautier C., Chollet A.M., Delagrange P., Danober L., Jockers R. Quantitative assessment of oligomeric amyloid beta peptide binding to alpha7 nicotinic receptor. Br. J. Pharm. 2019;176:3475-3488.

    Not in our library10.1111/bph.14688

  51. 51.

    Bencherif M., Lippiello P.M. Alpha7 neuronal nicotinic receptors: The missing link to understanding Alzheimer’s etiopathology? Med. Hypotheses. 2010;74:281-285.

    Not in our library10.1016/j.mehy.2009.09.011

  52. 52.

    Barykin E.P., Garifulina A.I., Kruykova E.V., Spirova E.N., Anashkina A.A., Adzhubei A.A., Shelukhina I.V., Kasheverov I.E., Mitkevich V.A., Kozin S.A., et al. Isomerization of Asp7 in Beta-Amyloid Enhances Inhibition of the alpha7 Nicotinic Receptor and Promotes Neurotoxicity. Cells. 2019;8:771.

    Not in our library10.3390/cells8080771

  53. 53.

    Takata K., Amamiya T., Mizoguchi H., Kawanishi S., Kuroda E., Kitamura R., Ito A., Saito Y., Tawa M., Nagasawa T., et al. Alpha7 nicotinic acetylcholine receptor-specific agonist DMXBA (GTS-21) attenuates Abeta accumulation through suppression of neuronal gamma-secretase activity and promotion of microglial amyloid-beta phagocytosis and ameliorates cognitive impairment in a mouse model of Alzheimer’s disease. Neurobiol. Aging. 2018;62:197-209.

    Not in our library10.1016/j.neurobiolaging.2017.10.021

  54. 54.

    Chang K.W., Zong H.F., Rizvi M.Y., Ma K.G., Zhai W., Wang M., Yang W.N., Ji S.F., Qian Y.H. Modulation of the MAPKs pathways affects Abeta-induced cognitive deficits in Alzheimer’s disease via activation of alpha7nAChR. Neurobiol. Learn. Mem. 2020;168:107154.

    Not in our library10.1016/j.nlm.2019.107154

  55. 55.

    Chang K.W., Zong H.F., Ma K.G., Zhai W.Y., Yang W.N., Hu X.D., Xu J.H., Chen X.L., Ji S.F., Qian Y.H. Activation of alpha7 nicotinic acetylcholine receptor alleviates Abeta1-42-induced neurotoxicity via downregulation of p38 and JNK MAPK signaling pathways. Neurochem. Int. 2018;120:238-250.

    Not in our library10.1016/j.neuint.2018.09.005

  56. 56.

    Kim T., Vidal G.S., Djurisic M., William C.M., Birnbaum M.E., Garcia K.C., Hyman B.T., Shatz C.J. Human LilrB2 is a beta-amyloid receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer’s model. Science. 2013;341:1399-1404.

    Not in our library10.1126/science.1242077

  57. 57.

    Cao Q., Shin W.S., Chan H., Vuong C.K., Dubois B., Li B., Murray K.A., Sawaya M.R., Feigon J., Black D.L., et al. Inhibiting amyloid-beta cytotoxicity through its interaction with the cell surface receptor LilrB2 by structure-based design. Nat. Chem. 2018;10:1213-1221.

    Not in our library10.1038/s41557-018-0147-z

  58. 58.

    Miyamoto T., Kim D., Knox J.A., Johnson E., Mucke L. Increasing the Receptor Tyrosine Kinase EphB2 Prevents Amyloid-beta-induced Depletion of Cell Surface Glutamate Receptors by a Mechanism That Requires the PDZ-binding Motif of EphB2 and Neuronal Activity. J. Biol. Chem. 2016;291:1719-1734.

    Not in our library10.1074/jbc.m115.666529

  59. 59.

    Hu R., Wei P., Jin L., Zheng T., Chen W.Y., Liu X.Y., Shi X.D., Hao J.R., Sun N., Gao C. Overexpression of EphB2 in hippocampus rescues impaired NMDA receptors trafficking and cognitive dysfunction in Alzheimer model. Cell Death Dis. 2017;8:e2717.

    Not in our library10.1038/cddis.2017.140

  60. 60.

    Lee M., Lee H.J., Park I.S., Park J.A., Kwon Y.J., Ryu Y.H., Kim C.H., Kang J.H., Hyun I.Y., Lee K.C., et al. Abeta pathology downregulates brain mGluR5 density in a mouse model of Alzheimer. Neuropharmacology. 2018;133:512-517.

    Not in our library10.1016/j.neuropharm.2018.02.003

  61. 61.

    Brody A.H., Strittmatter S.M. Synaptotoxic Signaling by Amyloid Beta Oligomers in Alzheimer’s Disease Through Prion Protein and mGluR5. Adv. Pharm. 2018;82:293-323.

    Not in our library10.1016/bs.apha.2017.09.007

  62. 62.

    Kayed R., Lasagna-Reeves C.A. Molecular mechanisms of amyloid oligomers toxicity. J. Alzheimers Dis. 2013;33:S67-S78.

    Not in our library10.3233/jad-2012-129001

  63. 63.

    Bode D.C., Baker M.D., Viles J.H. Ion Channel Formation by Amyloid-beta42 Oligomers but Not Amyloid-beta40 in Cellular Membranes. J. Biol. Chem. 2017;292:1404-1413.

    Not in our library10.1074/jbc.m116.762526

  64. 64.

    Bode D.C., Freeley M., Nield J., Palma M., Viles J.H. Amyloid-β oligomers have a profound detergent-like effect on lipid membrane bilayers, imaged by atomic force and electron microscopy. J. Biol. Chem. 2019;294:7566-7572.

    Not in our library10.1074/jbc.ac118.007195

  65. 65.

    Yasumoto T., Takamura Y., Tsuji M., Watanabe-Nakayama T., Imamura K., Inoue H., Nakamura S., Inoue T., Kimura A., Yano S., et al. High molecular weight amyloid beta1-42 oligomers induce neurotoxicity via plasma membrane damage. FASEB J. 2019;33:9220-9234.

    Not in our library10.1096/fj.201900604r

  66. 66.

    Dong X., Sun Y., Wei G., Nussinov R., Ma B. Binding of protofibrillar Abeta trimers to lipid bilayer surface enhances Abeta structural stability and causes membrane thinning. Phys. Chem. Chem. Phys. 2017;19:27556-27569.

    Not in our library10.1039/c7cp05959k

  67. 67.

    Jang H., Connelly L., Arce F.T., Ramachandran S., Kagan B.L., Lal R., Nussinov R. Mechanisms for the Insertion of Toxic, Fibril-like beta-Amyloid Oligomers into the Membrane. J. Chem. Theory Comput. 2013;9:822-833.

    Not in our library10.1021/ct300916f

  68. 68.

    Serra-Batiste M., Ninot-Pedrosa M., Bayoumi M., Gairi M., Maglia G., Carulla N. A beta 42 assembles into specific beta-barrel pore-forming oligomers in membrane-mimicking environments. Proc. Natl. Acad. Sci. USA. 2016;113:10866-10871.

    Not in our library10.1073/pnas.1605104113

  69. 69.

    Fernandez-Perez E.J., Sepulveda F.J., Peters C., Bascunan D., Riffo-Lepe N.O., Gonzalez-Sanmiguel J., Sanchez S.A., Peoples R.W., Vicente B., Aguayo L.G. Effect of Cholesterol on Membrane Fluidity and Association of Abeta Oligomers and Subsequent Neuronal Damage: A Double-Edged Sword. Front. Aging Neurosci. 2018;10:226.

    Not in our library10.3389/fnagi.2018.00226

  70. 70.

    Vahed M., Neya S., Matsuzaki K., Hoshino T. Analysis of Physicochemical Interaction of Abeta40 with a GM1 Ganglioside-Containing Lipid Membrane. J. Phys. Chem. B. 2018;122:3771-3781.

    Not in our library10.1021/acs.jpcb.8b00139

  71. 71.

    Hong S., Ostaszewski B.L., Yang T., O’Malley T.T., Jin M., Yanagisawa K., Li S., Bartels T., Selkoe D.J. Soluble Abeta oligomers are rapidly sequestered from brain ISF in vivo and bind GM1 ganglioside on cellular membranes. Neuron. 2014;82:308-319.

    Not in our library10.1016/j.neuron.2014.02.027

  72. 72.

    Lockhart C., Klimov D.K. Cholesterol Changes the Mechanisms of Abeta Peptide Binding to the DMPC Bilayer. J. Chem. Inf. Model. 2017;57:2554-2565.

    Not in our library10.1021/acs.jcim.7b00431

  73. 73.

    Fernandez-Perez E.J., Sepulveda F.J., Peoples R., Aguayo L.G. Role of membrane GM1 on early neuronal membrane actions of Abeta during onset of Alzheimer’s disease. Biochim. Biophys. Acta Mol. Basis Dis. 2017;1863:3105-3116.

    Not in our library10.1016/j.bbadis.2017.08.013

  74. 74.

    Dai Y., Zhang M., Shi X., Wang K., Gao G., Shen L., Sun T. Kinetic study of Abeta(1-42) amyloidosis in the presence of ganglioside-containing vesicles. Colloids Surf. B Biointerfaces. 2020;185:110615.

    Not in our library10.1016/j.colsurfb.2019.110615

  75. 75.

    Ferreira S.T., Klein W.L. The Abeta oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease. Neurobiol. Learn. Mem. 2011;96:529-543.

    Not in our library10.1016/j.nlm.2011.08.003

  76. 76.

    Sun J.L., Stokoe S.A., Roberts J.P., Sathler M.F., Nip K.A., Shou J., Ko K., Tsunoda S., Kim S. Co-activation of selective nicotinic acetylcholine receptors is required to reverse beta amyloid-induced Ca(2+) hyperexcitation. Neurobiol. Aging. 2019;84:166-177.

    Not in our library10.1016/j.neurobiolaging.2019.09.005

  77. 77.

    Gan K.J., Silverman M.A. Dendritic and axonal mechanisms of Ca2+ elevation impair BDNF transport in Abeta oligomer-treated hippocampal neurons. Mol. Biol. Cell. 2015;26:1058-1071.

    Not in our library10.1091/mbc.e14-12-1612

  78. 78.

    Shoshan-Barmatz V., De S., Meir A. The Mitochondrial Voltage-Dependent Anion Channel 1, Ca(2+) Transport, Apoptosis, and Their Regulation. Front. Oncol. 2017;7:60.

    Not in our library10.3389/fonc.2017.00060

  79. 79.

    Swerdlow R.H. Mitochondria and Mitochondrial Cascades in Alzheimer’s Disease. J. Alzheimers Dis. 2018;62:1403-1416.

    Not in our library10.3233/jad-170585

  80. 80.

    Du H., Guo L., Fang F., Chen D., Sosunov A.A., McKhann G.M., Yan Y., Wang C., Zhang H., Molkentin J.D., et al. Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease. Nat. Med. 2008;14:1097-1105.

    Not in our library10.1038/nm.1868

  81. 81.
    The Mitochondrial Calcium Uniporter Matches Energetic Supply with Cardiac Workload during Stress and Modulates Permeability Transition · 2015
    Not checked
  82. 82.

    Wang H., Zhang T., Ge X., Chen J., Zhao Y., Fu J. Parkin overexpression attenuates Abeta-induced mitochondrial dysfunction in HEK293 cells by restoring impaired mitophagy. Life Sci. 2020;244:117322.

    Not in our library10.1016/j.lfs.2020.117322

  83. 83.

    Youle R.J., Narendra D.P. Mechanisms of mitophagy. Nat. Rev. Mol. Cell Biol. 2011;12:9-14.

    Not in our library10.1038/nrm3028

  84. 84.

    Zhao N., Yan Q.W., Xia J., Zhang X.L., Li B.X., Yin L.Y., Xu B. Treadmill Exercise Attenuates Abeta-Induced Mitochondrial Dysfunction and Enhances Mitophagy Activity in APP/PS1 Transgenic Mice. Neurochem. Res. 2020;45:1202-1214.

    Not in our library10.1007/s11064-020-03003-4

  85. 85.

    Fang E.F., Hou Y., Palikaras K., Adriaanse B.A., Kerr J.S., Yang B., Lautrup S., Hasan-Olive M.M., Caponio D., Dan X., et al. Mitophagy inhibits amyloid-beta and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nat. Neurosci. 2019;22:401-412.

    Not in our library10.1038/s41593-018-0332-9

  86. 86.
    Impaired mitochondrial calcium efflux contributes to disease progression in models of Alzheimer’s disease · 2019
    No notice
  87. 87.
    Association of Amyloid and Tau With Cognition in Preclinical Alzheimer Disease · 2019
    No notice
  88. 88.

    Bateman R.J., Xiong C., Benzinger T.L., Fagan A.M., Goate A., Fox N.C., Marcus D.S., Cairns N.J., Xie X., Blazey T.M., et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N. Engl. J. Med. 2012;367:795-804.

    Not in our library10.1056/nejmoa1202753

  89. 89.

    Vermunt L., Sikkes S.A.M., van den Hout A., Handels R., Bos I., van der Flier W.M., Kern S., Ousset P.J., Maruff P., Skoog I., et al. Duration of preclinical, prodromal, and dementia stages of Alzheimer’s disease in relation to age, sex, and APOE genotype. Alzheimers Dement. 2019;15:888-898.

    Not in our library10.1016/j.jalz.2019.04.001

  90. 90.

    Ossenkoppele R., Smith R., Ohlsson T., Strandberg O., Mattsson N., Insel P.S., Palmqvist S., Hansson O. Associations between tau, A beta, and cortical thickness with cognition in Alzheimer disease. Neurology. 2019;92:E601-E612.

    Not in our library10.1212/wnl.0000000000006875

  91. 91.

    Hurtado D.E., Molina-Porcel L., Iba M., Aboagye A.K., Paul S.M., Trojanowski J.Q., Lee V.M. A{beta} accelerates the spatiotemporal progression of tau pathology and augments tau amyloidosis in an Alzheimer mouse model. Am. J. Pathol. 2010;177:1977-1988.

    Not in our library10.2353/ajpath.2010.100346

  92. 92.

    Forny-Germano L., Lyra e Silva N.M., Batista A.F., Brito-Moreira J., Gralle M., Boehnke S.E., Coe B.C., Lablans A., Marques S.A., Martinez A.M., et al. Alzheimer’s disease-like pathology induced by amyloid-beta oligomers in nonhuman primates. J. Neurosci. 2014;34:13629-13643.

    Not in our library10.1523/jneurosci.1353-14.2014

  93. 93.

    He Z., Guo J.L., McBride J.D., Narasimhan S., Kim H., Changolkar L., Zhang B., Gathagan R.J., Yue C., Dengler C., et al. Amyloid-beta plaques enhance Alzheimer’s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat. Med. 2018;24:29-38.

    Not in our library10.1038/nm.4443

  94. 94.

    Pontecorvo M.J., Devous M.D., Kennedy I., Navitsky M., Lu M., Galante N., Salloway S., Doraiswamy P.M., Southekal S., Arora A.K., et al. A multicentre longitudinal study of flortaucipir (18F) in normal ageing, mild cognitive impairment and Alzheimer’s disease dementia. Brain. 2019;142:1723-1735.

    Not in our library10.1093/brain/awz090

  95. 95.

    Zhang F., Gannon M., Chen Y., Yan S., Zhang S., Feng W., Tao J., Sha B., Liu Z., Saito T., et al. beta-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3beta/tau cascade. Sci. Transl. Med. 2020;12.

    Not in our library10.1126/scitranslmed.aay6931

  96. 96.

    Baek M.S., Cho H., Lee H.S., Choi J.Y., Lee J.H., Ryu Y.H., Lee M.S., Lyoo C.H. Temporal trajectories of in vivo tau and amyloid-beta accumulation in Alzheimer’s disease. Eur. J. Nucl. Med. Mol. Imaging. 2020.

    Not in our library10.1007/s00259-020-04773-3

  97. 97.

    Liu P., Reed M.N., Kotilinek L.A., Grant M.K.O., Forster C.L., Qiang W., Shapiro S.L., Reichl J.H., Chiang A.C.A., Jankowsky J.L., et al. Quaternary Structure Defines a Large Class of Amyloid-beta Oligomers Neutralized by Sequestration. Cell Rep. 2015;11:1760-1771.

    Not in our library10.1016/j.celrep.2015.05.021

  98. 98.

    Wang T., Xie X.X., Ji M., Wang S.W., Zha J., Zhou W.W., Yu X.L., Wei C., Ma S., Xi Z.Y., et al. Naturally occurring autoantibodies against A beta oligomers exhibited more beneficial effects in the treatment of mouse model of Alzheimer’s disease than intravenous immunoglobulin. Neuropharmacology. 2016;105:561-576.

    Not in our library10.1016/j.neuropharm.2016.02.015

  99. 99.

    Zhang X., Sun X.-X., Xue D., Liu D.-G., Hu X.-Y., Zhao M., Yang S.-G., Yang Y., Xia Y.-J., Wang Y., et al. Conformation-dependent scFv antibodies specifically recognize the oligomers assembled from various amyloids and show colocalization of amyloid fibrils with oligomers in patients with amyloidoses. Biochim. Et Biophys. Acta BBA Proteins Proteom. 2011;1814:1703-1712.

    Not in our library10.1016/j.bbapap.2011.09.005

  100. 100.

    Zhao M., Wang S.W., Wang Y.J., Zhang R., Li Y.N., Su Y.J., Zhou W.W., Yu X.L., Liu R.T. Pan-amyloid oligomer specific scFv antibody attenuates memory deficits and brain amyloid burden in mice with Alzheimer’s disease. Curr. Alzheimer Res. 2014;11:69-78.

    Not in our library10.2174/15672050113106660176

  101. 101.

    Brinkmalm G., Hong W., Wang Z., Liu W., O’Malley T.T., Sun X., Frosch M.P., Selkoe D.J., Portelius E., Zetterberg H., et al. Identification of neurotoxic cross-linked amyloid-beta dimers in the Alzheimer’s brain. Brain. 2019;142:1441-1457.

    Not in our library10.1093/brain/awz066

  102. 102.

    Jin M., Shepardson N., Yang T., Chen G., Walsh D., Selkoe D.J. Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc. Natl. Acad. Sci. USA. 2011;108:5819-5824.

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    Abdel-Hafiz L., Muller-Schiffmann A., Korth C., Fazari B., Chao O.Y., Nikolaus S., Schable S., Herring A., Keyvani K., Lamounier-Zepter V., et al. Abeta dimers induce behavioral and neurochemical deficits of relevance to early Alzheimer’s disease. Neurobiol. Aging. 2018;69:1-9.

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    Jana M.K., Cappai R., Pham C.L., Ciccotosto G.D. Membrane-bound tetramer and trimer Abeta oligomeric species correlate with toxicity towards cultured neurons. J. Neurochem. 2016;136:594-608.

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    Sherman M.A., LaCroix M., Amar F., Larson M.E., Forster C., Aguzzi A., Bennett D.A., Ramsden M., Lesne S.E. Soluble Conformers of Abeta and Tau Alter Selective Proteins Governing Axonal Transport. J. Neurosci. 2016;36:9647-9658.

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    Townsend M., Shankar G.M., Mehta T., Walsh D.M., Selkoe D.J. Effects of secreted oligomers of amyloid beta-protein on hippocampal synaptic plasticity: A potent role for trimers. J. Physiol. 2006;572:477-492.

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    Lesne S., Koh M.T., Kotilinek L., Kayed R., Glabe C.G., Yang A., Gallagher M., Ashe K.H. A specific amyloid-beta protein assembly in the brain impairs memory. Nature. 2006;440:352-357.

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    Amar F., Sherman M.A., Rush T., Larson M., Boyle G., Chang L., Gotz J., Buisson A., Lesne S.E. The amyloid-beta oligomer Abeta*56 induces specific alterations in neuronal signaling that lead to tau phosphorylation and aggregation. Sci. Signal. 2017;10.

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    A common mechanism of proteasome impairment by neurodegenerative disease-associated oligomers · 2018
    No notice
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    Ohnishi T., Yanazawa M., Sasahara T., Kitamura Y., Hiroaki H., Fukazawa Y., Kii I., Nishiyama T., Kakita A., Takeda H., et al. Na, K-ATPase alpha3 is a death target of Alzheimer patient amyloid-beta assembly. Proc. Natl. Acad. Sci. USA. 2015;112:E4465-E4474.

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    Wen J., Fang F., Guo S.H., Zhang Y., Peng X.L., Sun W.M., Wei X.R., He J.S., Hung T. Amyloid beta-Derived Diffusible Ligands (ADDLs) Induce Abnormal Autophagy Associated with Abeta Aggregation Degree. J. Mol. Neurosci. 2018;64:162-174.

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    Liu X., Teng Z., Cui C., Wang R., Liu M., Zhang Y. Amyloid beta-derived diffusible ligands (ADDLs) induce abnormal expression of insulin receptors in rat hippocampal neurons. J. Mol. Neurosci. 2014;52:124-130.

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    Herzer S., Meldner S., Rehder K., Grone H.J., Nordstrom V. Lipid microdomain modification sustains neuronal viability in models of Alzheimer’s disease. Acta Neuropathol. Commun. 2016;4:103.

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    Roberson E.D., Halabisky B., Yoo J.W., Yao J., Chin J., Yan F., Wu T., Hamto P., Devidze N., Yu G.Q., et al. Amyloid-beta/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer’s disease. J. Neurosci. 2011;31:700-711.

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    Mc Donald J.M., Savva G.M., Brayne C., Welzel A.T., Forster G., Shankar G.M., Selkoe D.J., Ince P.G., Walsh D.M., on behalf of the Medical Research Council Cognitive Function and Ageing Study. The presence of sodium dodecyl sulphate-stable Abeta dimers is strongly associated with Alzheimer-type dementia. Brain. 2010;133:1328-1341.

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    Kawarabayashi T., Shoji M., Younkin L.H., Wen-Lang L., Dickson D.W., Murakami T., Matsubara E., Abe K., Ashe K.H., Younkin S.G. Dimeric amyloid beta protein rapidly accumulates in lipid rafts followed by apolipoprotein E and phosphorylated tau accumulation in the Tg2576 mouse model of Alzheimer’s disease. J. Neurosci. 2004;24:3801-3809.

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    Shankar G.M., Leissring M.A., Adame A., Sun X., Spooner E., Masliah E., Selkoe D.J., Lemere C.A., Walsh D.M. Biochemical and immunohistochemical analysis of an Alzheimer’s disease mouse model reveals the presence of multiple cerebral Abeta assembly forms throughout life. Neurobiol. Dis. 2009;36:293-302.

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    Vazquez de la Torre A., Gay M., Vilaprinyo-Pascual S., Mazzucato R., Serra-Batiste M., Vilaseca M., Carulla N. Direct Evidence of the Presence of Cross-Linked Abeta Dimers in the Brains of Alzheimer’s Disease Patients. Anal. Chem. 2018;90:4552-4560.

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    O’Malley T.T., Witbold W.M., Linse S., Walsh D.M. The Aggregation Paths and Products of Abeta42 Dimers Are Distinct from Those of the Abeta42 Monomer. Biochemistry. 2016;55:6150-6161.

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    Meilandt W.J., Cisse M., Ho K., Wu T., Esposito L.A., Scearce-Levie K., Cheng I.H., Yu G.Q., Mucke L. Neprilysin overexpression inhibits plaque formation but fails to reduce pathogenic Abeta oligomers and associated cognitive deficits in human amyloid precursor protein transgenic mice. J. Neurosci. 2009;29:1977-1986.

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    Kreutzer A.G., Yoo S., Spencer R.K., Nowick J.S. Stabilization, Assembly, and Toxicity of Trimers Derived from Abeta. J. Am. Chem. Soc. 2017;139:966-975.

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    Reed M.N., Hofmeister J.J., Jungbauer L., Welzel A.T., Yu C., Sherman M.A., Lesne S., LaDu M.J., Walsh D.M., Ashe K.H., et al. Cognitive effects of cell-derived and synthetically derived Abeta oligomers. Neurobiol. Aging. 2011;32:1784-1794.

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    Cheng I.H., Scearce-Levie K., Legleiter J., Palop J.J., Gerstein H., Bien-Ly N., Puolivali J., Lesne S., Ashe K.H., Muchowski P.J., et al. Accelerating amyloid-beta fibrillization reduces oligomer levels and functional deficits in Alzheimer disease mouse models. J. Biol. Chem. 2007;282:23818-23828.

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    Oddo S., Caccamo A., Tran L., Lambert M.P., Glabe C.G., Klein W.L., LaFerla F.M. Temporal profile of amyloid-beta (Abeta) oligomerization in an in vivo model of Alzheimer disease. A link between Abeta and tau pathology. J. Biol. Chem. 2006;281:1599-1604.

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    Yoo S.J., Lee J.H., Kim S.Y., Son G., Kim J.Y., Cho B., Yu S.W., Chang K.A., Suh Y.H., Moon C. Differential spatial expression of peripheral olfactory neuron-derived BACE1 induces olfactory impairment by region-specific accumulation of beta-amyloid oligomer. Cell Death Dis. 2017;8:e2977.

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    Hoshi M., Sato M., Matsumoto S., Noguchi A., Yasutake K., Yoshida N., Sato K. Spherical aggregates of beta-amyloid (amylospheroid) show high neurotoxicity and activate tau protein kinase I/glycogen synthase kinase-3beta. Proc. Natl. Acad. Sci. USA. 2003;100:6370-6375.

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    Parthasarathy S., Inoue M., Xiao Y., Matsumura Y., Nabeshima Y., Hoshi M., Ishii Y. Structural Insight into an Alzheimer’s Brain-Derived Spherical Assembly of Amyloid beta by Solid-State NMR. J. Am. Chem. Soc. 2015;137:6480-6483.

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    Noguchi A., Matsumura S., Dezawa M., Tada M., Yanazawa M., Ito A., Akioka M., Kikuchi S., Sato M., Ideno S., et al. Isolation and characterization of patient-derived, toxic, high mass amyloid beta-protein (Abeta) assembly from Alzheimer disease brains. J. Biol. Chem. 2009;284:32895-32905.

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    Komura H., Kakio S., Sasahara T., Arai Y., Takino N., Sato M., Satomura K., Ohnishi T., Nabeshima Y.I., Muramatsu S.I., et al. Alzheimer Abeta Assemblies Accumulate in Excitatory Neurons upon Proteasome Inhibition and Kill Nearby NAKalpha3 Neurons by Secretion. iScience. 2019;13:452-477.

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    Gong Y., Chang L., Viola K.L., Lacor P.N., Lambert M.P., Finch C.E., Krafft G.A., Klein W.L. Alzheimer’s disease-affected brain: Presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc. Natl. Acad. Sci. USA. 2003;100:10417-10422.

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    Chang L., Bakhos L., Wang Z., Venton D.L., Klein W.L. Femtomole immunodetection of synthetic and endogenous amyloid-beta oligomers and its application to Alzheimer’s disease drug candidate screening. J. Mol. Neurosci. 2003;20:305-313.

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    Lambert M.P., Velasco P.T., Chang L., Viola K.L., Fernandez S., Lacor P.N., Khuon D., Gong Y.S., Bigio E.H., Shaw P., et al. Monoclonal antibodies that target pathological assemblies of A beta. J. Neurochem. 2007;100:23-35.

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    Xie Z., Shapiro L.P., Cahill M.E., Russell T.A., Lacor P.N., Klein W.L., Penzes P. Kalirin-7 prevents dendritic spine dysgenesis induced by amyloid beta-derived oligomers. Eur. J. Neurosci. 2019;49:1091-1101.

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    Henley D., Raghavan N., Sperling R., Aisen P., Raman R., Romano G. Preliminary Results of a Trial of Atabecestat in Preclinical Alzheimer’s Disease. N. Engl. J. Med. 2019;380:1483-1485.

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    Doody R.S., Raman R., Farlow M., Iwatsubo T., Vellas B., Joffe S., Kieburtz K., He F., Sun X.Y., Thomas R.G., et al. A Phase 3 Trial of Semagacestat for Treatment of Alzheimer’s Disease. N. Engl. J. Med. 2013;369:341-350.

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    Salloway S., Sperling R., Fox N.C., Blennow K., Klunk W., Raskind M., Sabbagh M., Honig L.S., Porsteinsson A.P., Ferris S., et al. Two Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer’s Disease. N. Engl. J. Med. 2014;370:322-333.

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    Honig L.S., Vellas B., Woodward M., Boada M., Bullock R., Borrie M., Hager K., Andreasen N., Scarpini E., Liu-Seifert H., et al. Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease. New Engl. J. Med. 2018;378:321-330.

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    Persistent neuropathological effects 14 years following amyloid-β immunization in Alzheimer’s disease · 2019
    No notice

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