Grant: CIHR Fellowship

Alzheimer's disease (AD) is a progressive neurodegenerative disease which is the leading cause of dementia in the elderly. The cause of AD remains disputed, resulting in the lack of successful therapeutics. This is a grave concern, given the increase in life expectancy and the large number of baby boomers entering the age at which AD tends to manifest. AD is confirmed by aggregates of the protein beta-amyloid (Abeta), which are toxic to neurons. Glutamate is the major excitatory brain neurotransmitter which plays a critical role in learning and memory formation; the dysregulation of its receptor, mGluR5 has been implicated in AD. Abeta binding to mGluR5, can stimulate the release of calcium inside neurons, and inhibits autophagy, the process of removal of misfolded, damaged, or toxic proteins. This can result in neuronal death and subsequent cognitive decline. Women are more predisposed to developing AD when compared to age and risk-matched men, but the cause of this predisposition remains unclear. Our lab has shown that inhibiting mGluR5 can improve AD symptoms in male AD mice, but not in female mice. Similarly, we have also observed that Abeta does not bind to mGluR5 in female AD mice, like they do in males. Therefore, we plan to determine whether other proteins bind differently in male vs female mice. We will also examine whether calcium release from internal stores are altered differentially in male vs female AD mice. Excessive calcium release from the internal stores is buffered by the mitochondria, the powerhouse of the cell. Mitochondria are critical to cells with high energy demand like the neurons, and mitochondrial damage has been observed in AD. Here, we will determine if there is a sex-difference in mitochondrial health and whether this is due to a change in autophagy and/or calcium signaling. This will provide us a better understanding of the sex-differences in the progression of AD, allowing for better drug development and clinical trial design