Diet-induced hyperhomocysteinemia increases amyloid-β formation and deposition in a mouse model of Alzheimer's disease

J. M. Zhuo, G. S. Portugal, W. D. Kruger, H. Wang, Thomas J. Gould, D. Praticò

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Hyperhomocysteinemia (HHcy) has been recognized as a risk factor for developing Alzheimer's disease (AD). However, its underlying molecular mechanisms are still elusive. Here we show that HHcy induces an elevation of amyloid beta (Aβ) levels and deposition, as well as behavioral impairments, in a mouse model of AD-like amyloidosis, the Tg2576 mice. This elevation is not associated with significant change of the steady state levels of the Aβ precursor protein (APP), β- or α-secretase pathways, nor with the Aβ catabolic pathways. By contrast, HHcy significantly reduces glycogen synthase kinase 3 (GSK3) Ser21/9 phosphorylation, but not total GSK3 protein levels. Similar results are obtained in brains homogenates from a genetic mouse model of HHcy. In vitro studies show that homocysteine increases Aβ formation, reduces phosphorylated GSK3 levels, without changes in total APP and its metabolism, and these effects are prevented by selective GSK3 inhibition. Overall, these data support a potential link between GSK3 and the pro-amyloidotic effect of HHcy in vivo and in vitro.

Original languageEnglish (US)
Pages (from-to)140-149
Number of pages10
JournalCurrent Alzheimer Research
Volume7
Issue number2
DOIs
StatePublished - Mar 1 2010

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Glycogen Synthase Kinase 3
Hyperhomocysteinemia
Amyloid
Alzheimer Disease
Diet
Protein Precursors
Amyloid Precursor Protein Secretases
Genetic Models
Homocysteine
Amyloidosis
Phosphorylation
Brain
Proteins

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology

Cite this

Zhuo, J. M. ; Portugal, G. S. ; Kruger, W. D. ; Wang, H. ; Gould, Thomas J. ; Praticò, D. / Diet-induced hyperhomocysteinemia increases amyloid-β formation and deposition in a mouse model of Alzheimer's disease. In: Current Alzheimer Research. 2010 ; Vol. 7, No. 2. pp. 140-149.
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Diet-induced hyperhomocysteinemia increases amyloid-β formation and deposition in a mouse model of Alzheimer's disease. / Zhuo, J. M.; Portugal, G. S.; Kruger, W. D.; Wang, H.; Gould, Thomas J.; Praticò, D.

In: Current Alzheimer Research, Vol. 7, No. 2, 01.03.2010, p. 140-149.

Research output: Contribution to journalArticle

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