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 over-expression 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.

Age‐dependent impact of CaV3.2 T‐type calcium channel deletion on myogenic tone and flow‐mediated vasodilatation in small arteries

“…An age‐related down‐regulation of Ca V 3.1 mRNA and protein expression was previously demonstrated in the brains of humans and mice (Rice et al . ). This down‐regulation of Ca V 3.1 protein might be considered to play a role in the age‐dependent effect of Ca V 3.2 channels in both MT and FMVD (e.g.…”

Ca2+homeostasis dysregulation in Alzheimer's disease: a focus on plasma membrane and cell organelles

“…burden, whereas overexpression of Ca v 3.1 T-type VGCC alleviates amyloidogenesis (86). Consistently, the Ca v 3.1 T-type VGCC enhancer, ST101, is reported to induce APP cleavage in vitro (87) and contribute to cognitive improvement in vivo (88).…”

“…Additionally, Ab peptides may intensify N-and P-type Ca 2+ current (83)(84)(85). As for the Ca V 3.1 T-type VGCC, its age-related down-regulation in human brain tissue was revealed by Rice et al (86), and the presence of AD exacerbates the alteration. In the subsequent experiments on 3 xTg-AD mice and cultured cells, the researchers further demonstrated that inhibition of the channel increases Ab Figure 2.…”

Amyloid Beta Peptides Block New Synapse Assembly by Nogo Receptor-Mediated Inhibition of T-Type Calcium Channels

“…T-type channels expression is down regulated in the brain during aging and AD (Rice et al, 2014), suggesting reduced function of these channels may be key in driving calcium dysfunction in AD. Further, chronic inhibition of T-type channels increases Aβ peptide levels, suggesting T-type channel activity is linked with Aβ production.…”