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

Neurobiol Aging 2014

Rice RA, Berchtold NC, Cotman CW

Abstract

  1. Neurobiol Aging. 2014 May;35(5):1002-11. doi: 10.1016/j.neurobiolaging.2013.10.090. Epub 2013 Oct 30.

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

Rice RA(1), Berchtold NC(1), Cotman CW(1), Green KN(2).

Author information: (1)Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USA. (2)Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USA. Electronic address: kngreen@uci.edu.

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.

Copyright © 2014 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.neurobiolaging.2013.10.090 PMCID: PMC3939046 PMID: 24268883 [Indexed for MEDLINE]

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