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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 Aβ 42  activates the TRPM2 channel to induce neurotoxicity in mouse hippocampal neurons. Aβ 42 -induced neurotoxicity was ablated by genetic knockout (TRPM2-KO) and attenuated by inhibition of the TRPM2 channel activity or activation through PARP-1. Aβ 42 -induced neurotoxicity was also inhibited by treatment with TPEN used as a Zn 2+ -specific chelator. Cell imaging revealed that Aβ 42 -induced lysosomal dysfunction, cytosolic Zn 2+  increase, mitochondrial Zn 2+  accumulation, loss of mitochondrial function, and mitochondrial generation of ROS. These effects were suppressed by TRPM2-KO, inhibition of TRPM2 or PARP-1, or treatment with TPEN. Bafilomycin-induced lysosomal dysfunction also resulted in TRPM2-dependent cytosolic Zn 2+  increase, mitochondrial Zn 2+  accumulation, and mitochondrial generation of ROS, supporting that lysosomal dysfunction and accompanying Zn 2+  release trigger mitochondrial Zn 2+  accumulation and generation of ROS. Aβ 42 -induced effects on lysosomal and mitochondrial functions besides neurotoxicity were also suppressed by inhibition of PKC and NOX. Furthermore, Aβ 42 -induced neurotoxicity was prevented by inhibition of MEK/ERK. Therefore, our study reveals multiple molecular mechanisms, including PKC/NOX-mediated generation of ROS, activation of MEK/ERK and PARP-1, lysosomal dysfunction and Zn 2+  release, mitochondrial Zn 2+  accumulation, loss of mitochondrial function, and mitochondrial generation of ROS, are critically engaged in forming a positive feedback loop that drives Aβ 42 -induced activation of the TRPM2 channel and neurotoxicity in hippocampal neurons. These findings shed novel and mechanistic insights into AD pathogenesis.

cell death and disease

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