Grant: Doctoral: Vanier Canada Graduate Scholarships

Disorders in fat, or lipid, metabolism are now recognized to play a key role in brain disorders including Alzheimer's Disease (AD), the most common type of dementia. Previously, most studies focused on the roles of brain lipids in the development of dementia, and, despite knowing that circulating lipids affect dementia risk, the contributions of blood lipids to AD have largely been ignored. Specifically, in humans, elevated levels of low-density lipoprotein (LDL), also known as "bad" cholesterol, are associated with a higher risk of AD. Humans typically have 70-80% of their total cholesterol in LDL and the other 20-30% in high-density lipoprotein (HDL), or "good" cholesterol. Oppositely, mice, which are frequently used in animal models of AD to study AD development and test therapies, have 80% of their circulating cholesterol in HDL. This prevents us from effectively studying how circulating lipids contribute to the development of AD. The reason why mouse "good" to "bad" cholesterol ratio is different from humans is that mice are naturally deficient in cholesteryl ester transfer protein (CETP), the activity of which raises LDL and lowers HDL. Our project aims to "humanize" mouse blood lipid profile by crossing transgenic mice that express CETP with established models of AD. By using techniques such as preclinical magnetic resonance imaging (MRI) and novel 3D microscopy of blood vessels in the brain, we aim to understand how putting back CETP into mice affects the development and progression of amyloid plaques (one of the defining features of AD) and changes in the blood vessel network in the brain. We expect that CETP expression will worsen the hallmarks of AD in mice. If so, in the future, we can test CETP inhibitors, which are already being tested for use in cardiovascular diseases, as an effective intervention to improve AD-related outcomes.