Grant: Doctoral: Vanier Canada Graduate Scholarships

Alzheimer's disease (AD) is the most common form of senile dementia, affecting over 40% of people over 85 years old in North America. As the aging population increases, it is expected that AD will evolve into a health crisis if no effective treatments are discovered. A leading hypothesis for the pathogenesis of AD is that the abnormal metabolism of beta-amyloid (AB) peptides triggers many of the neurotoxic events in AD including cell death, inflammation, and the formation of amyloid plaques, a major neuropathological hallmark. Because increased production of AB accounts for only 5% of AD cases, age-related defects in AB clearance are thought to underlie its accumulation for most patients. We propose a novel strategy to promote AB clearance and neuronal recovery using synthetic brain high-density lipoprotein (HDL). HDL is composed of lipids (fats), which are surrounded and stabilized by a protein component that aid their transport within the body. Lipids are critical to maintain neurons, specialized cells in the brain. As adult neurons cannot synthesize sufficient lipids to survive, they depend upon lipid transported on brain HDL particles secreted by surrounding glial cells. Mobilization of brain HDL is critical following neuronal injury as it helps to remove excess, potentially toxic, lipids that are released from damaged cells. It has recently been shown that naturally occurring brain HDL are also capable of enhancing AB degradation. Additionally, treatment of AD mouse models with drugs known to enhance the concentration and lipid content of HDL decreases AB levels and restores cognitive function. However, these drugs also induce negative side effects rendering them unsafe for human use. In this proposal we will avoid these side effects by directly adding recombinant HDL to affected animals and cell culture systems to enhance AB degradation and promote neuronal repair. This approach may yield a therapeutic platform for treatment of AD with minimal side effects.