Diet-induced hyperhomocysteinemia increases amyloid-beta formation and deposition in a mouse model of Alzheimer's disease.
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 (Abeta) 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 Abeta precursor protein (APP), beta- or alpha-secretase pathways, nor with the Abeta 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 Abeta 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.
Zhuo
J-M
JM
Department of Pharmacology, Neuroscience Program Temple University School of Medicine, Philadelphia, PA 19140, USA.
Portugal
G S
GS
Kruger
W D
WD
Wang
H
H
Gould
T J
TJ
Pratico
D
D
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000595:Amino Acid Sequence / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D005526:Food, Formulated / Q000009:adverse effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006710:Homocysteine / Q000097:blood* / Q000633:toxicity; D020138:Hyperhomocysteinemia / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000378:metabolism; D012694:Serine / Q000378:metabolism
D016229:Amyloid beta-Peptides; D006710:Homocysteine; D012694:Serine; D038362:Glycogen Synthase Kinase 3