Lianne Trigiani, Montreal Neurological Institute

Supervisor: Edith Hamel, Montreal Neurological Institute

Vascular dementia (VaD) and Alzheimer’s disease (AD) involve a cerebrovascular pathology characterized by structural alterations of the vessel wall, degenerating capillaries, and vascular fibrosis. These characteristics are found in transgenic mice that overexpress transforming growth factor-β1 (TGF mice), and result in reduced dilatory function, baseline perfusion, and impaired hyperemic response to increased neuronal activity. It was recently found that a compromised cerebral circulation, when combined with a risk factor for VaD or AD such as high cholesterol, worsened cerebrovascular deficits and precipitated cognitive failure, which can be rescued using a brain-penetrating statin, simvastatin. Interestingly, physical exercise can improve cognitive function both in young and older adults as well as in AD animal models. We hypothesize that i) physical exercise will be as effective as simvastatin to improve cognitive and cerebrovascular function in TGF mice fed a high cholesterol diet (HCD), and ii) induction of cognitive deficits by a HCD and subsequent rescuing of cognitive function will be dependent on both age and gender. The main objective of the proposed study is to compare the efficacy of voluntary physical exercise to the pharmacological treatment of simvastatin in how they counteract the deleterious effects of hypercholesterolemia in TGF mice. We will use young male and female TGF mice together with corresponding groups of wild-type (WT) age-matched littermate controls. The study will include 4 groups for each genotype: one group will be fed a standard diet; the remaining 3 will be rendered hypercholesterolemic. Of these 3 hypercholesterolemic groups, one will be untreated, the second group will have access to a spinning wheel, and the third group will receive simvastatin. All groups will undergo treatment (exercise or simvastatin) or remain untreated for 3 months. Outcome behavioural measures will include spatial learning and memory testing in the Morris water maze and novel object recognition. A subset of mice from each group will be used to assess cerebrovascular function by measuring cerebral blood flow and cerebrovascular reactivity. Brain tissue collected from these mice will be used for Western blot analyses and to measure brain-cholesterol levels. Remaining mice will be injected with BrdU prior to being perfused to quantify hippocampal neurogenesis. To examine other potential cellular mechanisms at play, immunohistochemical analyses will be used to identify inflammatory and oxidative stress markers in grey (cortex and hippocampus) and white matter (internal capsule, corpus callosum). Many elderly may be unaware of an underlying hypercholesterolemic pathology, and are thus ignorant of their increased susceptibility to cognitive decline. Due to the current absence of a disease-modifying therapeutic treatment for AD or VaD, it is crucial to investigate non-pharmacological preventative or curative approaches. Although strong evidence exists to support an association between regular physical activity and lower risk of developing dementia, very little is known about underlying molecular mechanisms of these benefits reaped by physical exercise. We will investigate the underlying cellular mechanisms of deficit induction, benefit of drug action and healthy lifestyle habits, and hopefully provide future clinical studies with a new therapeutic target.