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

NEUROBIOLOGY OF AGING

卷:35

Article

Rice, Rachel A.¹  Berchtold, Nicole C.¹  Cotman, Carl W.¹  Green, Kim N.¹ 

[1] Univ Calif Irvine, Dept Neurobiol & Behav, Inst Memory Impairments & Neurol Disorders, Irvine, CA 92697 USA

关键词: Aging;    Alzheimer's disease;    Calcium;    T-type calcium channel;    APP processing;    Amyloid;    Calpains;   

DOI  :  10.1016/j.neurobiolaging.2013.10.090

来源: Elsevier

【 摘 要 】

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. (C) 2014 Elsevier Inc. All rights reserved.

【 授权许可】

Free