Apolipoprotein E4 effects in Alzheimer’s disease are mediated by synaptotoxic oligomeric amyloid-β

Koffie, Robert M.; Hashimoto, Tadafumi; Tai, Hwan-Ching; Kay, Kevin R.; Serrano-Pozo, Alberto; Joyner, Daniel; Hou, Steven; Kopeikina, Katherine J.; Frosch, Matthew P.; Lee, Virginia M.; Holtzman, David M.; Hyman, Bradley T.; Spires-Jones, Tara L.

doi:10.1093/brain/aws127

Cited by 327Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Apolipoprotein E4 effects in Alzheimer’s disease are mediated by synaptotoxic oligomeric amyloid-β

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Koffie, Robert M., Hashimoto, Tadafumi, Tai, Hwan-Ching, Kay, Kevin R., Serrano-Pozo, Alberto, Joyner, Daniel, Hou, Steven, Kopeikina, Katherine J. +5 more·2012·Brain

DOI 10.1093/brain/aws127PMC PMC3381721

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Abstract

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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apoE, especially its apoE4 isoform, facilitates the formation of Aβ oligomers.
“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]
Several recent studies provided evidence to support increased content of Aβ oligomers in the extracellular space in brains of patients with AD expressing human ApoE4 isoform, and intraneuronally in mice expressing human ApoE4 isoform after inhibition of Aβ-degrading enzyme neprilysin.
“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]
APOE4 is associated with increased oligomerization and deposition of Aβ in vitro and in vivo.
“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]
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.
“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]

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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: Koffie, Robert M.
Hashimoto, Tadafumi
Tai, Hwan-Ching
Frosch, Matthew P.
Holtzman, David M.
Hyman, Bradley T.
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
DOI: 10.1093/brain/aws127
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: Health Sciences › Medicine › Physiology › 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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Apolipoprotein E4 effects in Alzheimer’s disease are mediated by synaptotoxic oligomeric amyloid-β

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