Multiple molecular mechanisms form a positive feedback loop driving amyloid β42 peptide-induced neurotoxicity via activation of the TRPM2 channel in hippocampal neurons.

ABSTRACT: Emerging evidence supports an important role for the ROS-sensitive TRPM2 channel in mediating age-related cognitive impairment in Alzheimer's disease (AD), particularly neurotoxicity resulting from generation of excessive neurotoxic Aβ peptides. Here we examined the elusive mechanisms by which Aβ42 activates the TRPM2 channel to induce neurotoxicity in mouse hippocampal neurons. Aβ42-induced neurotoxicity was ablated by genetic knockout (TRPM2-KO) and attenuated by inhibition of the TRPM2 channel activity or activation through PARP-1. Aβ42-induced neurotoxicity was also inhibited by treatment with TPEN used as a Zn2+-specific chelator. Cell imaging revealed that Aβ42-induced lysosomal dysfunction, cytosolic Zn2+ increase, mitochondrial Zn2+ accumulation, loss of mitochondrial function, and

SUBMITTER: Li X 

PROVIDER: S-EPMC5833848 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature