Age-related downregulation of the CaV3.1 T-type calcium channel as a mediator of amyloid beta production

作者：Rice Rachel A; Berchtold Nicole C; Cotman Carl W; Green Kim N^*

来源：Neurobiology of Aging, 2014, 35(5): 1002-1011.

DOI：10.1016/j.neurobiolaging.2013.10.090

• Aging
• Alzheimer's disease
• Calcium
• T-type calcium channel
• APP processing
• Amyloid
• Calpains

Alzheimer's is a crippling neurodegenerative disease that largely affects aged individuals. Decades of research have highlighted age-related changes in calcium homeostasis that occur before and throughout the duration of the disease, and the contributions of such dysregulation to Alzheimer's disease pathogenesis. We report an age-related decrease in expression of the CaV3.1 T-type calcium channel at the level of messenger RNA and protein in both humans and mice that is exacerbated with the presence of Alzheimer's disease. Downregulating T-type calcium channels in N2a cells and the 3xTg-AD mouse model of Alzheimer's disease, by way of pharmacologic inhibition with NNC-55-0396, results in a rapid increase in amyloid beta production via reductions in non-amyloidogenic processing, whereas genetic overexpression of the channel in human embryonic kidney cells expressing amyloid precursor protein produces complementary effects. The age-related decline in CaV3.1 expression may therefore contribute to a pro-amyloidogenic environment in the aging brain and represents a novel opportunity to intervene in the course of Alzheimer's disease pathogenesis.

• 出版日期2014-5