Apolipoprotein E4 effects in Alzheimer's disease are mediated by synaptotoxic oligomeric amyloid-β.
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 cognitive decline in Alzheimer's disease.
Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, MA 02129, USA.
Robert M
RM
Koffie
Tadafumi
T
Hashimoto
Hwan-Ching
HC
Tai
Kevin R
KR
Kay
Alberto
A
Serrano-Pozo
Daniel
D
Joyner
Steven
S
Hou
Katherine J
KJ
Kopeikina
Matthew P
MP
Frosch
Virginia M
VM
Lee
David M
DM
Holtzman
Bradley T
BT
Hyman
Tara L
TL
Spires-Jones
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000502:physiology*; D053318:Apolipoprotein E3 / Q000235:genetics; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D005838:Genotype; D006801:Humans; D009410:Nerve Degeneration / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism; D061251:Primary Cell Culture; D021381:Protein Transport; D013569:Synapses / Q000378:metabolism / Q000473:pathology*
D016229:Amyloid beta-Peptides; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4