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 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 Zn2+ increase, mitochondrial Zn2+ accumulation, and mitochondrial generation of ROS, supporting that lysosomal dysfunction and accompanying Zn2+ release trigger mitochondrial Zn2+ accumulation and generation of ROS. Aβ42-induced effects on lysosomal and mitochondrial functions besides neurotoxicity were also suppressed by inhibition of PKC and NOX. Furthermore, Aβ42-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 Zn2+ release, mitochondrial Zn2+ accumulation, loss of mitochondrial function, and mitochondrial generation of ROS, are critically engaged in forming a positive feedback loop that drives Aβ42-induced activation of the TRPM2 channel and neurotoxicity in hippocampal neurons. These findings shed novel and mechanistic insights into AD pathogenesis.
Highlights
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by progressive cognitive impairments and representing the most prevalent cause of dementia among the elder people
Scale bar is 10 μm. i Summary of the mean DCFH fluorescence intensity in neurons under indicated conditions normalized to the basal or CTL level, from four independent experiments with each experiment examining 10–15 neurons for each conditions. *p < 0.05 indicates difference from CTL. †p < 0.05; and †††p < 0.005 indicate difference from that in neurons exposed with Aβ42 alone induced neurotoxicity, we examined the effects of inhibiting protein kinase C (PKC) and NADPH-dependent oxidases (NOX) on Aβ42-induced increase in the [Zn2+]c, lysosomal dysfunction, mitochondrial Zn2+
Scale bar is 10 μm. b, g Summary of the mean fluorescence intensity of FluoZin[3] or LysoTracker under indicated conditions normalized to that in neurons exposed to Aβ42 alone, from three to four independent experiments with each experiment examining 10–12 neurons for each condition. *p < 0.05; **p < 0.01; and ***p < 0.005 indicate difference from neurons exposed with Aβ42 alone. c, h Representative confocal images showing RhodZin[3] and MitoTracker staining in hippocampal neurons exposed to 1 μM Aβ42 for 48 h with or without 10 nM Gö6976 c, 30 μM apocynin or 10 μM GKT137831 h
Summary
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by progressive cognitive impairments and representing the most prevalent cause of dementia among the elder people. One histopathological hallmark of AD is the formation of senile amyloid plaque with deposits of amyloid β (Aβ) peptides resulting from proteolytic cleavage of amyloid precursor protein (APP). Official journal of the Cell Death Differentiation Association. Li and Jiang Cell Death and Disease (2018)9:195 by presenilin-1 (PS-1) containing γ-secretase[1]. It is known that Aβ induce neurotoxicity via multiple but yet not fully understood mechanisms, leading to synaptic loss and network dysfunction in hippocampus and other brain regions[2]. Lipid peroxides and oxidative modifications of proteins and lipids are widely observed in cells exposed to. Aβ and in the brain of transgenic APP/PS-1 AD mice, consistent with a role for oxidative stress in Aβ-induced neurotoxicity[4,5].
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