Role of Apolipoprotein E in β-Amyloidogenesis: ISOFORM-SPECIFIC EFFECTS ON PROTOFIBRIL TO FIBRIL CONVERSION OF Aβ IN VITRO AND BRAIN Aβ DEPOSITION IN VIVO.
Human APOE ϵ4 allele is a strong genetic risk factor of Alzheimer disease. Neuropathological and genetic studies suggested that apolipoprotein E4 (apoE4) protein facilitates deposition of amyloid β peptide (Aβ) in the brain, although the mechanism whereby apoE4 increases amyloid aggregates remains elusive. Here we show that injection of Aβ protofibrils induced Aβ deposition in the brain of APP transgenic mice, suggesting that Aβ protofibrils acted as a seed for aggregation and deposition of Aβ in vivo. Injection of Aβ protofibrils together with apoE3 significantly attenuated Aβ deposition, whereas apoE4 did not have this effect. In vitro assays revealed that the conversion of Aβ protofibrils to fibrils progressed more slowly upon coincubation with apoE2 or apoE3 compared with that with apoE4. Aβ protofibrils complexed with apoE4 were less stable than those with apoE2 or apoE3. These data suggest that the suppression effect of apoE2 or apoE3 on the structural conversion of Aβ protofibrils to fibrils is stronger than those of apoE4, thereby impeding β-amyloid deposition.
From the Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences and.
Yukiko
Y
Hori
From the Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences and the Department of Neuropathology, Graduate School of Medicine, University of Tokyo, Tokyo, 113-0033 Japan and the Department of Neurology/Alzheimer's Disease Research Unit, Massachusetts General Hospital, Charlestown, Massachusetts 02129.
Tadafumi
T
Hashimoto
From the Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences and.
Hidetoshi
H
Nomoto
the Department of Neurology/Alzheimer's Disease Research Unit, Massachusetts General Hospital, Charlestown, Massachusetts 02129.
Bradley T
BT
Hyman
From the Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences and the Department of Neuropathology, Graduate School of Medicine, University of Tokyo, Tokyo, 113-0033 Japan and iwatsubo@m.u-tokyo.ac.jp.
Takeshi
T
Iwatsubo
D000682:Amyloid / Q000096:biosynthesis* / Q000737:chemistry; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology*; D001921:Brain / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D020033:Protein Isoforms / Q000502:physiology*
D000682:Amyloid; D001057:Apolipoproteins E; D020033:Protein Isoforms
Alzheimer disease; amyloid; amyloid-β; apolipoprotein E; protein stability