Endogenous Amyloid-formed Ca2+-permeable Channels in Aged 3xTg AD Mice.

Abstract

Alzheimer's disease (AD), the leading cause of dementia, is characterized by the accumulation of beta-amyloid peptides (Aβ). However, whether Aβ itself is a key toxic agent in AD pathogenesis and the precise mechanism of Aβ-elicited neurotoxicity are still debated. Emerging evidence demonstrates that the Aβ channel/pore hypothesis could explain Aβ toxicity, because Aβ oligomers are able to disrupt membranes and cause edge-conductivity pores that may disrupt cell Ca²⁺ homeostasis and drive neurotoxicity in AD. However, all available data to support this hypothesis have been collected from "in vitro" experiments using high concentrations of exogenous Aβ. It is still unknown whether Aβ channels can be formed by endogenous Aβ in AD animal models. Here, we report an unexpected finding of the spontaneous Ca²⁺ oscillations in aged 3xTg AD mice but not in age-matched wild-type mice. These spontaneous Ca²⁺ oscillations are sensitive to extracellular Ca²⁺, ZnCl₂, and the Aβ channel blocker Anle138b, suggesting that these spontaneous Ca²⁺ oscillations in aged 3xTg AD mice are mediated by endogenous Aβ-formed channels.