期刊
CURRENT ALZHEIMER RESEARCH
卷 7, 期 2, 页码 140-149出版社
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/156720510790691326
关键词
Amyloid metabolism; amyloid beta; Tg2576 mice; glycogen synthase kinase 3
资金
- National Institute of Health [AG-22512, HLBI-16327]
- Alzheimer's Association
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [T32HL091804] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG022512] Funding Source: NIH RePORTER
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.
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