Master of Science
Dr. Marco Prado and Dr. John MacDonald
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the progressive deterioration of memory and other intellectual abilities. Accumulation of amyloid-β (Aβ) peptide, the major contributor to the senile plaques central to AD, is thought to mediate neurotoxicity by inducing oxidative stress and calcium dysregulation. Transient Receptor Potential Melastatin type 2 (TRPM2) is a calcium permeable, non-selective cation channel activated under oxidative stress and ultimately induces cell death. The APPSWE/PSEN1ΔE9 double transgenic mouse model carries the human APPswe (Swedish mutations K594N/M595L) and PS1 mutations with a deletion in exon 9 (PS1-dE9), and is one of the most commonly used AD model. Both mutations have been shown to be linked to Familial (early onset) AD as well as an increased production in Aβ peptides. We propose that TRPM2 contributes to pathological deficits in AD. To test this, we crossed TRPM2 knock-out with APPSWE/PSEN1ΔE9 mice to generate four mouse genotypes (WT, TRPM2 knock-out, Alzheimer’s and Alzheimer’s TRPM2 knock-out). We hypothesize that Alzheimer’s TRPM2 knock-out mice will have improved memory performance when compared to Alzheimer’s mice. To test this hypothesis, anxiety, motor activity, recognition memory, as well as spatial learning and memory were tested in these mutant mice at 3, 6, 9, 12, and 15 months of age. For these assessments we use open field locomotor activity (OFT), elevated plus maze (Elev+), object recognition (OR), Barnes (BM) and Morris water maze (MWM) respectively. Our data showed that no genotype difference was observed in OFT, Elev+ and OR in terms of hyperactivity, anxiety, and recognition memory. On the other hand, our data indicate that Alzheimer’s mice show cognitive impairment (spatial memory deficit) compared to WT controls while Alzheimer’s mice without TRPM2 do not, suggesting that elimination of TRPM2 activity prevents the spatial learning and memory deficits observed in APPSWE/PSEN1ΔE9 double transgenic mice.
Chen, Megan M., "Contribution of TRPM2 to Memory Loss in an Alzheimer's Mouse Model" (2013). Electronic Thesis and Dissertation Repository. 1772.