title: Age-related downregulation of the CaV3.1 T-type calcium channel as a mediator of amyloid beta production.
abstract: 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.
authors.affiliation: Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USA.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Rice
authors.affiliation: Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USA.
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Berchtold
authors.affiliation: Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USA.
authors.forename: Carl W
authors.initials: CW
authors.lastname: Cotman
authors.affiliation: Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USA. Electronic address: kngreen@uci.edu.
authors.forename: Kim N
authors.initials: KN
authors.lastname: Green
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics / Q000517:prevention & control; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D012333:RNA, Messenger / Q000378:metabolism; D055815:Young Adult
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C121855:CACNA1G protein, human; D020747:Calcium Channels, T-Type; D012333:RNA, Messenger; D002118:Calcium
keywords: APP processing; Aging; Alzheimer's disease; Amyloid; Calcium; Calpains; T-type calcium channel