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- Title
Apolipoprotein E4 effects in Alzheimer’s disease are mediated by synaptotoxic oligomeric amyloid-β.
- Authors
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.
- 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 >50 000 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 cognitive decline in Alzheimer’s disease.
- Subjects
APOLIPOPROTEIN E4; ALZHEIMER'S disease; AMYLOID beta-protein; NEURODEGENERATION; BRAIN tomography; SYNAPSES; COGNITION
- Publication
Brain: A Journal of Neurology, 2012, Vol 135, Issue 7, p2155
- ISSN
0006-8950
- Publication type
Article
- DOI
10.1093/brain/aws127