Homocysteine, another risk factor for Alzheimer disease, impairs apolipoprotein E3 function.
Apolipoprotein E (apoE) ε4 and hyperhomocysteinemia are risk factors for Alzheimer disease (AD). The dimerization of apoE3 by disulfide bonds between cysteine residues enhances apoE3 function to generate HDL. Because homocysteine (Hcy) harbors a thiol group, we examined whether Hcy interferes with the dimerization of apoE3 and thereby impairs apoE3 function. We found that Hcy inhibits the dimerization of apoE3 and reduces apoE3-mediated HDL generation to a level similar to that by apoE4, whereas Hcy does not affect apoE4 function. Western blot analysis of cerebrospinal fluid showed that the ratio of apoE3 dimers was significantly lower in the samples from the patients with hyperhomocysteinemia than in those that from control subjects. Hyperhomocysteinemia induced by subcutaneous injection of Hcy to apoE3 knock-in mice decreased the level of the apoE3 dimer in the brain homogenate. Because apoE-HDL plays a role in amyloid β-protein clearance, these results suggest that two different risk factors, apoE4 and hyperhomocysteinemia, may share a common mechanism that accelerates the pathogenesis of AD in terms of reduced HDL generation.
Minagawa
Hirohisa
H
Department of Alzheimer Disease Research, National Center for Geriatrics and Gerontology, 35 Gengo, Morioka, Obu, Aichi 474-8511, Japan.
Watanabe
Atsushi
A
Akatsu
Hiroyasu
H
Adachi
Kayo
K
Ohtsuka
Chigumi
C
Terayama
Yasuo
Y
Hosono
Takashi
T
Takahashi
Satoshi
S
Wakita
Hideaki
H
Jung
Cha-Gyun
CG
Komano
Hiroto
H
Michikawa
Makoto
M
D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D053318:Apolipoprotein E3 / Q000134:cerebrospinal fluid* / Q000235:genetics; D053327:Apolipoprotein E4 / Q000134:cerebrospinal fluid / Q000235:genetics; D001921:Brain / Q000378:metabolism; D004220:Disulfides / Q000134:cerebrospinal fluid; D006710:Homocysteine / Q000134:cerebrospinal fluid* / Q000235:genetics; D006801:Humans; D020138:Hyperhomocysteinemia / Q000134:cerebrospinal fluid / Q000139:chemically induced / Q000235:genetics; D008075:Lipoproteins, HDL / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D055503:Protein Multimerization; D012307:Risk Factors
D016229:Amyloid beta-Peptides; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D004220:Disulfides; D008075:Lipoproteins, HDL; D006710:Homocysteine