The Transient Receptor Potential Melastatin 2 (TRPM2) Channel Contributes to β-Amyloid Oligomer-Related Neurotoxicity and Memory Impairment

In Alzheimer9s disease, accumulation of soluble oligomers of β-amyloid peptide is known to be highly toxic, causing disturbances in synaptic activity and neuronal death. Multiple studies relate these effects to increased oxidative stress and aberrant activity of calcium-permeable cation channels leading to calcium imbalance. The transient receptor potentialmelastatin 2 ( TRPM2) channel, a Ca 2+ -permeable nonselective cation channel activated by oxidative stress, has been implicated in neurodegenerative diseases, and more recently in amyloid-induced toxicity. Here we show that the function of TRPM2is augmented by treatment of cultured neurons with β-amyloid oligomers. Aged APP/PS1 Alzheimer9s mouse model showed increased levels of endoplasmic reticulum stress markers, protein disulfide isomeraseand phosphorylated eukaryotic initiation factor2α, as well as decreased levels of the presynaptic marker synaptophysin. Elimination of TRPM2in APP/PS1 mice corrected these abnormal responses without affecting plaque burden. These effects of TRPM2seem to be selective for β-amyloid toxicity, as ER stress responses to thapsigarginor tunicamycinin TRPM2−/− neurons was identical to that of wild-type neurons. Moreover, reduced microglial activation was observed in TRPM2−/− /APP/PS1 hippocampus compared with APP/PS1 mice. In addition, age-dependent spatial memorydeficits in APP/PS1 mice were reversed in TRPM2−/− /APP/PS1 mice. These results reveal the importance of TRPM2for β-amyloid neuronal toxicity, suggesting that TRPM2activity could be potentially targeted to improve outcomes in Alzheimer9s disease. SIGNIFICANCE STATEMENT Transient receptor potentialmelastatin 2 ( TRPM2) is an oxidative stress sensing calcium-permeable channel that is thought to contribute to calcium dysregulation associated with neurodegenerative diseases, including Alzheimer9s disease. Here we show that oligomeric β-amyloid, the toxic peptide in Alzheimer9s disease, facilitates TRPM2channel activation. In mice designed to model Alzheimer9s disease, genetic elimination of TRPM2normalized deficits in synaptic markers in aged mice. Moreover, the absence of TRPM2improved age-dependent spatial memorydeficits observed in Alzheimer9s mice. Our results reveal the importance of TRPM2for neuronal toxicity and memory impairments in an Alzheimer9s mouse model and suggest that TRPM2could be targeted for the development of therapeutic agents effective in the treatment of dementia.