Diet-induced hyperhomocysteinemia increases amyloid-beta formation and deposition in a mouse model of Alzheimer's disease.
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 (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.
Citations
Related Concepts
Related Feeds
Alzheimer's Disease: Animal Models
Alzheimer's disease is a neurodegenerative disease which can be studied using various experimental systems. This feed focuses on animal models used for Alzheimer's disease research.
Alzheimer's Disease: APP
Amyloid precursor protein (APP) proteolysis is critical for the development of Alzheimer's disease, a neurodegenerative disease associated with accumulation of amyloid plaques in the brain. Here is the latest research on APP and Alzheimer's disease.
Alzheimer's Disease: Amyloid Beta
Alzheimer's disease is a neurodegenerative disease associated with the accumulation of amyloid plaques in the brain; these plaques are comprised of amyloid beta deposits. Here is the latest research in this field.