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Apolipoprotein E4 effects in Alzheimer’s disease are mediated by synaptotoxic oligomeric amyloid-β
Open accessAbstract
The apolipoprotein E ε4 gene is the most important genetic risk factor for sporadic Alzheimer's disease, but the link between this gene and neurodegeneration remains unclear. Using array tomography, we analysed >50000 synapses in brains of 11 patients with Alzheimer's disease and five non-demented control subjects and found that synapse loss around senile plaques in Alzheimer's disease correlates with the burden of oligomeric amyloid-β in the neuropil and that this synaptotoxic oligomerized peptide is present at a subset of synapses. Further analysis reveals apolipoprotein E ε4 patients with Alzheimer's disease have significantly higher oligomeric amyloid-β burden and exacerbated synapse loss around plaques compared with apolipoprotein E ε3 patients. Apolipoprotein E4 protein colocalizes with oligomeric amyloid-β and enhances synaptic localization of oligomeric amyloid-β by >5-fold. Biochemical characterization shows that the amyloid-β enriched at synapses by apolipoprotein E4 includes sodium dodecyl sulphate-stable dimers and trimers. In mouse primary neuronal culture, lipidated apolipoprotein E4 enhances oligomeric amyloid-β association with synapses via a mechanism involving apolipoprotein E receptors. Together, these data suggest that apolipoprotein E4 is a co-factor that enhances the toxicity of oligomeric amyloid-β both by increasing its levels and directing it to synapses, providing a link between apolipoprotein E ε4 genotype and synapse loss, a major correlate of cogn…
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In the citing paper
“It has been recently appreciated that apoE, especially its apoE4 isoform, facilitates the formation of Aβ oligomers [33,34].”
From Blocking the apoE/Aβ interaction ameliorates Aβ-related pathology in APOE ε2 and ε4 targeted replacement Alzheimer model mice (2014) · cites this paper as [34]
In the citing paper
“Several recent studies provided evidence to support increased content of Ab oligomers in the extracellular space in brains of patients with AD, expressing the human ApoE4 isoform, 37,38 and intraneuronally in mice expressing human ApoE4 isoform after inhibition of Ab-degrading enzyme neprilysin.39”
From Blocking the Interaction between Apolipoprotein E and Aβ Reduces Intraneuronal Accumulation of Aβ and Inhibits Synaptic Degeneration (2013) · cites this paper as [38]
In the citing paper
“APOE4 is associated with increased oligomerization and deposition of Aβ in vitro and in vivo113,115,192”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [192]
In the citing paper
“Previous studies have reported higher microglia numbers within the radius of 20-30μm from the plaque edge and significant synapse loss within the distance of 20μm from the plaque edge 10 .”
From ABI3 deletion in TgCRND8 mice is associated with reduced amyloid plaque pathology and altered glial response (2023) · cites this paper as [10]
In the citing paper
“This interaction assessed biophysically, in the postmortem brain from individuals with Alzheimer’s disease, corroborates in vitro and in vivo evidence of displacement of amyloid-β oligomers [64], representing a potential mechanism of action underlying the protection against amyloid-β oligomer-induced synaptic degradation [153,154,155,156,157] observed with S2R modulators [64].”
From Sigma-2 Receptors—From Basic Biology to Therapeutic Target: A Focus on Age-Related Degenerative Diseases (2023) · cites this paper as [153]
In the citing paper
“We and others have observed that oligomeric amyloid beta (Aβ) peptide causes synaptic dysfunction, accumulates within in synapses, and is associated with synapse loss around plaques [34, 41, 52, 60, 64].”
From Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease (2024) · cites this paper as [34]
In the citing paper
“We and others have observed that oligomeric amyloid beta (Aβ) peptide causes synaptic dysfunction, accumulates within in synapses, and is associated with synapse loss around plaques [34, 41, 52, 60, 64].”
From Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease (2024) · cites this paper as [34]
In the citing paper
“We and others have observed that oligomeric amyloid beta (Aβ) peptide causes synaptic dysfunction, accumulates within in synapses, and is associated with synapse loss around plaques [34, 41, 52, 60, 64].”
From Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease (2024) · cites this paper as [34]
In the citing paper
“It has been shown that Aβ can be found in synapses of Alzheimer’s cases [6, 29, 34, 51, 65, 66], but the mechanisms by which Aβ induces synaptic toxicity remain unclear.”
From Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease (2024) · cites this paper as [34]
In the citing paper
“The structural state of Aβ labelled with 6E10 antibody(monomer, oligomer or fibril) recognised in the present array tomography studies is not clear, which is a limitation of the study, but we have confirmed the interaction of TMEM7 with NAB61, an antibody that preferentially recognises fibrillar oligomers and reacts with synaptic oligomeric Aβ [34].”
From Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease (2024) · cites this paper as [34]
In the citing paper
“As previously described [34], post-synaptic terminal density was reduced in AD (Fig. 1B, 7% reduction in PSD density F[1,28.73] = 4.36, p = 0.046, no significant sex differences).”
From Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease (2024) · cites this paper as [34]
In the citing paper
“In AD cases, images were acquired with a plaque in the field since our previous work demonstrated that synaptic Aβ accumulation is most prominent around plaques [29, 34].”
From Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease (2024) · cites this paper as [34]
In the citing paper
“The structural state of Aβ labelled with 6E10 antibody(monomer, oligomer or fibril) recognised in the present array tomography studies is not clear, which is a limitation of the study, but we have confirmed the interaction of TMEM7 with NAB61, an antibody that preferentially recognises fibrillar oligomers and reacts with synaptic oligomeric Aβ [34].”
From Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease (2024) · cites this paper as [34]
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Metadata
- Authors
- Koffie, R. M., Hashimoto, T., Tai, H.-C., Kay, K. R., Serrano-Pozo, A., Joyner, D., Hou, S., Kopeikina, K. J., Frosch, M. P., Lee, V. M., Holtzman, D. M., Hyman, B. T., & Spires-Jones, T. L.
- Affiliations
- Harvard University (US)
- Boston University (US)
- University of Pennsylvania (US)
- Washington University in St. Louis (US)
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-05-25
- Volume
- 135
- Issue
- 7
- Pages
- 2155-2168
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC3381721
- OpenAlex
- W2169135478
- Cited by
- 327
- References
- 56
- Citations by year
- 2026: 14 · 2025: 24 · 2024: 25 · 2023: 33 · 2022: 39 · 2021: 23 · 2020: 18 · 2019: 23 · 2018: 18 · 2017: 20 · 2016: 17 · 2015: 15 · 2014: 21 · 2013: 30 · 2012: 7
- FWCI
- 15.65
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Brain (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Drug Discovery Foundation
- Japan Society for the Promotion of Science (24800015)
- National Institute on Aging (AG-08487, AG033670-01A1, R00AG033670, AG 12406, P50AG005134, P30AG062421)
- National Institute of General Medical Sciences (T32 GM07753, T32GM007753)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- APOE ε4, Alzheimer's disease, amyloid-beta oligomers, synaptic loss, synaptotoxicity, amyloid plaques, apolipoprotein E receptor, genetic risk factors, cognitive decline
- MeSH terms
- Alzheimer Disease, Genotype, Humans, Nerve Degeneration, Neurons, Synapses, Case-Control Studies, Amyloid beta-Peptides, Protein Transport, Apolipoprotein E3, Apolipoprotein E4, Plaque, Amyloid, Primary Cell Culture
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