Homocysteine, another risk factor for Alzheimer disease, impairs apolipoprotein E3 function

Hirohisa Minagawa, Atsushi Watanabe, Hiroyasu Akatsu, Kayo Adachi, Chigumi Ohtsuka, Yasuo Terayama, Takashi Hosono, Satoshi Takahashi, Hideaki Wakita, Cha Gyun Jung, Hiroto Komano, Makoto Michikawa

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Apolipoprotein E (apoE) ∈4 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.

Original languageEnglish
Pages (from-to)38382-38388
Number of pages7
JournalJournal of Biological Chemistry
Volume285
Issue number49
DOIs
Publication statusPublished - 03-12-2010

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Apolipoprotein E3
Homocysteine
Alzheimer Disease
Apolipoprotein E4
Hyperhomocysteinemia
Dimerization
Dimers
Cerebrospinal fluid
Amyloidogenic Proteins
Apolipoproteins E
Subcutaneous Injections
Ports and harbors
Sulfhydryl Compounds
Disulfides
Cysteine
Cerebrospinal Fluid
Brain
Western Blotting

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Minagawa, H., Watanabe, A., Akatsu, H., Adachi, K., Ohtsuka, C., Terayama, Y., ... Michikawa, M. (2010). Homocysteine, another risk factor for Alzheimer disease, impairs apolipoprotein E3 function. Journal of Biological Chemistry, 285(49), 38382-38388. https://doi.org/10.1074/jbc.M110.146258
Minagawa, Hirohisa ; Watanabe, Atsushi ; Akatsu, Hiroyasu ; Adachi, Kayo ; Ohtsuka, Chigumi ; Terayama, Yasuo ; Hosono, Takashi ; Takahashi, Satoshi ; Wakita, Hideaki ; Jung, Cha Gyun ; Komano, Hiroto ; Michikawa, Makoto. / Homocysteine, another risk factor for Alzheimer disease, impairs apolipoprotein E3 function. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 49. pp. 38382-38388.
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Minagawa, H, Watanabe, A, Akatsu, H, Adachi, K, Ohtsuka, C, Terayama, Y, Hosono, T, Takahashi, S, Wakita, H, Jung, CG, Komano, H & Michikawa, M 2010, 'Homocysteine, another risk factor for Alzheimer disease, impairs apolipoprotein E3 function', Journal of Biological Chemistry, vol. 285, no. 49, pp. 38382-38388. https://doi.org/10.1074/jbc.M110.146258

Homocysteine, another risk factor for Alzheimer disease, impairs apolipoprotein E3 function. / Minagawa, Hirohisa; Watanabe, Atsushi; Akatsu, Hiroyasu; Adachi, Kayo; Ohtsuka, Chigumi; Terayama, Yasuo; Hosono, Takashi; Takahashi, Satoshi; Wakita, Hideaki; Jung, Cha Gyun; Komano, Hiroto; Michikawa, Makoto.

In: Journal of Biological Chemistry, Vol. 285, No. 49, 03.12.2010, p. 38382-38388.

Research output: Contribution to journalArticle

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T1 - Homocysteine, another risk factor for Alzheimer disease, impairs apolipoprotein E3 function

AU - Minagawa, Hirohisa

AU - Watanabe, Atsushi

AU - Akatsu, Hiroyasu

AU - Adachi, Kayo

AU - Ohtsuka, Chigumi

AU - Terayama, Yasuo

AU - Hosono, Takashi

AU - Takahashi, Satoshi

AU - Wakita, Hideaki

AU - Jung, Cha Gyun

AU - Komano, Hiroto

AU - Michikawa, Makoto

PY - 2010/12/3

Y1 - 2010/12/3

N2 - Apolipoprotein E (apoE) ∈4 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.

AB - Apolipoprotein E (apoE) ∈4 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.

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Minagawa H, Watanabe A, Akatsu H, Adachi K, Ohtsuka C, Terayama Y et al. Homocysteine, another risk factor for Alzheimer disease, impairs apolipoprotein E3 function. Journal of Biological Chemistry. 2010 Dec 3;285(49):38382-38388. https://doi.org/10.1074/jbc.M110.146258