Project 453006

Alzheimer's disease (AD) is a disorder that results in degeneration of the brain, which leads to severe memory impairments. The most common form of the disease occurs in individuals older than 65 years, and elicits personal and societal costs that are immeasurable and growing as the population grows older. The common and central features of AD include deposition of Amyloid-ß (Aß) in brain cells. Recent studies using an Aß mouse model have shown that AD brains show increased cleavage of a class of RNA biomolecules, called SINE RNAs, which, when intact, act as molecular brakes that inactivate abnormal expression of genes. Although the relationship between accelerated cleavage of SINE RNAs, gene expression deregulation, neural network abnormalities and the behavioral consequences are less known, it is fundamentally important to understand these early molecular changes in the brain as they may provide a target for therapeutic interventions early in the progression of the disease before significant and irreversible brain damage occurs. In particular, this work will use more advanced mouse models to provide new understanding of how SINE RNA cleavage contributes to altered gene expression, disrupted neuronal activity and behavioral and cognitive impairment in AD. Our hypothesis is that faster cleavage of the brain's SINE RNAs is a key driver of changes that ultimately lead to the descent into dementia. The proposed work will provide spatial and temporal evidence of the occurred changes, and will pinpoint a target for treatments that could halt or slow devastating effects of AD from occurring. Coupled with the lack of effective treatments and the aging population, the fact that over 747,000 Canadians are suffering from dementia, including AD, points out the importance and urgency for medical breakthroughs to slow or cure the disease.