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Zhuo JM , Portugal GS , Kruger WD , Wang H , Gould TJ , Pratico D
Diet-Induced Hyperhomocysteinemia Increases Amyloid-beta Formation and Deposition in a Mouse Model of Alzheimer's Disease
Current Alzheimer Research. 2010 Mar;7(2) :140-149
PMID: ISI:000275518400005   
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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 (A beta) 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 A beta precursor protein (APP), beta- or alpha-secretase pathways, nor with the A beta 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 A beta 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. Portugal, G. S. Kruger, W. D. Wang, H. Gould, T. J. Pratico, D. National Institute of Health [AG-22512, HLBI-16327]; Alzheimer's Association This work was funded by grants from the National Institute of Health, AG-22512 (D.P.), HLBI-16327 (W.D.K.), and the Alzheimer's Association (D.P.). We also appreciate the support of Pennsylvania Commonwealth to the Fox Chase Cancer Center. The authors wish to thank Ms. Ni Meng, and Daiyan Mao for technical assistance. 38 Bentham science publ ltd; executive ste y26, po box 7917, saif zone, 1200 br sharjah, u arab 568jk