TY - JOUR
T1 - Diet-induced hyperhomocysteinemia increases amyloid-β formation and deposition in a mouse model of Alzheimer's disease
AU - Zhuo, J. M.
AU - Portugal, G. S.
AU - Kruger, W. D.
AU - Wang, H.
AU - Gould, T. J.
AU - Praticò, D.
PY - 2010/3
Y1 - 2010/3
N2 - 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.
AB - 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.
KW - Amyloid metabolism
KW - Amyloid β
KW - Glycogen synthase kinase 3
KW - Tg2576 mice
UR - http://www.scopus.com/inward/record.url?scp=77949675424&partnerID=8YFLogxK
U2 - 10.2174/156720510790691326
DO - 10.2174/156720510790691326
M3 - Article
C2 - 19939226
SN - 1567-2050
VL - 7
SP - 140
EP - 149
JO - Current Alzheimer Research
JF - Current Alzheimer Research
IS - 2
ER -