title: The Transient Receptor Potential Melastatin 2 (TRPM2) Channel Contributes to β-Amyloid Oligomer-Related Neurotoxicity and Memory Impairment.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Molecular Medicine, Robarts Research Institute, Department of Physiology and Pharmacology, Schulich School of Medicine, and.
authors.forename: Valeriy G
authors.identifier: http://orcid.org/0000-0002-3629-7702
authors.initials: VG
authors.lastname: Ostapchenko
authors.affiliation: Molecular Medicine, Robarts Research Institute.
authors.forename: Megan
authors.initials: M
authors.lastname: Chen
authors.affiliation: Molecular Medicine, Robarts Research Institute, Department of Physiology and Pharmacology, Schulich School of Medicine, and.
authors.forename: Monica S
authors.initials: MS
authors.lastname: Guzman
authors.affiliation: Department of Pharmacology and Therapeutics, College of Medicine, University of Manitoba, Winnipeg, Manitoba R3E 0T6, Canada, Neuroscience Research Group, Kleysen Institute for Advanced Medicine, University of Manitoba, Winnipeg, Manitoba R3E 3J7, Canada, and.
authors.forename: Yu-Feng
authors.initials: YF
authors.lastname: Xie
authors.affiliation: Department of Pharmacology and Therapeutics, College of Medicine, University of Manitoba, Winnipeg, Manitoba R3E 0T6, Canada, Neuroscience Research Group, Kleysen Institute for Advanced Medicine, University of Manitoba, Winnipeg, Manitoba R3E 3J7, Canada, and.
authors.forename: Natalie
authors.initials: N
authors.lastname: Lavine
authors.affiliation: Molecular Medicine, Robarts Research Institute.
authors.forename: Jue
authors.initials: J
authors.lastname: Fan
authors.affiliation: Molecular Medicine, Robarts Research Institute.
authors.forename: Flavio H
authors.initials: FH
authors.lastname: Beraldo
authors.affiliation: Molecular Medicine, Robarts Research Institute.
authors.forename: Amanda C
authors.identifier: http://orcid.org/0000-0002-2760-3069
authors.initials: AC
authors.lastname: Martyn
authors.affiliation: Molecular Medicine, Robarts Research Institute.
authors.forename: Jillian C
authors.initials: JC
authors.lastname: Belrose
authors.affiliation: Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mori
authors.affiliation: Molecular Medicine, Robarts Research Institute, Department of Physiology and Pharmacology, Schulich School of Medicine, and Department of Anatomy and Cell Biology, Schulich School of Medicine, University of Western Ontario, London, Ontario N6A 5B7, Canada.
authors.forename: John F
authors.initials: JF
authors.lastname: MacDonald
authors.affiliation: Molecular Medicine, Robarts Research Institute, Department of Physiology and Pharmacology, Schulich School of Medicine, and Department of Anatomy and Cell Biology, Schulich School of Medicine, University of Western Ontario, London, Ontario N6A 5B7, Canada, mprado@robarts.ca vprado@robarts.ca michael.jackson@umanitoba.ca.
authors.forename: Vania F
authors.identifier: http://orcid.org/0000-0003-4994-6393
authors.initials: VF
authors.lastname: Prado
authors.affiliation: Molecular Medicine, Robarts Research Institute, Department of Physiology and Pharmacology, Schulich School of Medicine, and Department of Anatomy and Cell Biology, Schulich School of Medicine, University of Western Ontario, London, Ontario N6A 5B7, Canada, mprado@robarts.ca vprado@robarts.ca michael.jackson@umanitoba.ca.
authors.forename: Marco A M
authors.identifier: http://orcid.org/0000-0002-3028-5778
authors.initials: MA
authors.lastname: Prado
authors.affiliation: Molecular Medicine, Robarts Research Institute, Department of Physiology and Pharmacology, Schulich School of Medicine, and Department of Pharmacology and Therapeutics, College of Medicine, University of Manitoba, Winnipeg, Manitoba R3E 0T6, Canada, Neuroscience Research Group, Kleysen Institute for Advanced Medicine, University of Manitoba, Winnipeg, Manitoba R3E 3J7, Canada, and mprado@robarts.ca vprado@robarts.ca michael.jackson@umanitoba.ca.
authors.forename: Michael F
authors.identifier: http://orcid.org/0000-0002-4730-201X
authors.initials: MF
authors.lastname: Jackson
mesh_terms: D000544:Alzheimer Disease / Q000139:chemically induced / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000378:metabolism; D050053:TRPM Cation Channels / Q000172:deficiency* / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D050053:TRPM Cation Channels; C544443:TRPM2 protein, mouse
keywords: Alzheimer's disease; TRPM2; cognitive impairment; mouse model; neurotoxicity; β-amyloid