title: Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid β peptide.
abstract: Alzheimer's disease (AD) is the most common progressive neurodegenerative disorder causing dementia. Massive deposition of amyloid β peptide (Aβ) as senile plaques in the brain is the pathological hallmark of AD, but oligomeric, soluble forms of Aβ have been implicated as the synaptotoxic component. The apolipoprotein E ε 4 (apoE ε4) allele is known to be a genetic risk factor for developing AD. However, it is still unknown how apoE impacts the process of Aβ oligomerization. Here, we found that the level of Aβ oligomers in APOE ε4/ε4 AD patient brains is 2.7 times higher than those in APOE ε3/ε3 AD patient brains, matched for total plaque burden, suggesting that apoE4 impacts the metabolism of Aβ oligomers. To test this hypothesis, we examined the effect of apoE on Aβ oligomer formation. Using both synthetic Aβ and a split-luciferase method for monitoring Aβ oligomers, we observed that apoE increased the level of Aβ oligomers in an isoform-dependent manner (E2 < E3 < E4). This effect appears to be dependent on the ApoE C-terminal domain. Moreover, these results were confirmed using endogenous apoE isolated from the TBS-soluble fraction of human brain, which increased the formation of Aβ oligomers. Together, these data show that lipidated apoE, especially apoE4, increases Aβ oligomers in the brain. Higher levels of Aβ oligomers in the brains of APOE ε4/ε4 carriers compared with APOE ε3/ε3 carriers may increase the loss of dendritic spines and accelerate memory impairments, leading to earlier cognitive decline in AD.
authors.affiliation: Department of Neurology, Alzheimer's Disease Research Unit, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
authors.forename: Tadafumi
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Alberto
authors.initials: A
authors.lastname: Serrano-Pozo
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Hori
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Adams
authors.forename: Shuko
authors.initials: S
authors.lastname: Takeda
authors.forename: Adrian Olaf
authors.initials: AO
authors.lastname: Banerji
authors.forename: Akinori
authors.initials: A
authors.lastname: Mitani
authors.forename: Daniel
authors.initials: D
authors.lastname: Joyner
authors.forename: Diana H
authors.initials: DH
authors.lastname: Thyssen
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Bacskai
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Frosch
authors.forename: Tara L
authors.initials: TL
authors.lastname: Spires-Jones
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Finn
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000704:Analysis of Variance; D053329:Apolipoprotein E2 / Q000235:genetics / Q000378:metabolism; D053318:Apolipoprotein E3 / Q000235:genetics / Q000378:metabolism; D053327:Apolipoprotein E4 / Q000235:genetics* / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics; D057809:HEK293 Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008297:Male; D060172:Morpholinos / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D060172:Morpholinos; D010446:Peptide Fragments; D020033:Protein Isoforms; C075222:amyloid beta-protein (1-42); D049452:Green Fluorescent Proteins