In Alzheimer's 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 potential melastatin 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 TRPM2 is augmented 
by treatment of cultured neurons with β-amyloid oligomers. Aged APP/PS1 
Alzheimer's mouse model showed increased levels of endoplasmic reticulum stress 
markers, protein disulfide isomerase and phosphorylated eukaryotic initiation 
factor 2α, as well as decreased levels of the presynaptic marker synaptophysin. 
Elimination of TRPM2 in APP/PS1 mice corrected these abnormal responses without 
affecting plaque burden. These effects of TRPM2 seem to be selective for 
β-amyloid toxicity, as ER stress responses to thapsigargin or tunicamycin in 
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 memory deficits in APP/PS1 
mice were reversed in TRPM2(-/-)/APP/PS1 mice. These results reveal the 
importance of TRPM2 for β-amyloid neuronal toxicity, suggesting that TRPM2 
activity could be potentially targeted to improve outcomes in Alzheimer's 
disease.
SIGNIFICANCE STATEMENT: Transient receptor potential melastatin 2 (TRPM2) is an 
oxidative stress sensing calcium-permeable channel that is thought to contribute 
to calcium dysregulation associated with neurodegenerative diseases, including 
Alzheimer's disease. Here we show that oligomeric β-amyloid, the toxic peptide 
in Alzheimer's disease, facilitates TRPM2 channel activation. In mice designed 
to model Alzheimer's disease, genetic elimination of TRPM2 normalized deficits 
in synaptic markers in aged mice. Moreover, the absence of TRPM2 improved 
age-dependent spatial memory deficits observed in Alzheimer's mice. Our results 
reveal the importance of TRPM2 for neuronal toxicity and memory impairments in 
an Alzheimer's mouse model and suggest that TRPM2 could be targeted for the 
development of therapeutic agents effective in the treatment of dementia.