Grant: Project Grant

There is still no cure to Alzheimer's Disease (AD) and diagnosis is mostly based on cognitive function. We now know that cognitive function is affected late in the progression of the disease. Detection at a much earlier state than currently achieved is needed. Our understanding of the disease was largely focused on abnormal concentrations of certain proteins in the brain. Treatments designed to regulate these proteins have all failed. We suggest harnessing latest discoveries on AD where inflammation of the blood vessels of the brain is a cause for this disease (and others) and is a potential new target for the treatment, and perhaps even for the prevention of the disease. The first goal is to apply advanced imaging methods such as magnetic resonance imaging to detect key players in the processes leading to brain dysfunction in three different live animal models of AD. In particular, we will image a cerebrovascular inflammation marker - vascular cell adhesion molecule-1 (VCAM-1) - to show that it can be detected prior to any other sign of abnormality (including activation of microglia). These studies will include a thorough assessment (using RNA-seq) of changes in the brains. Behavioural studies of those animals are expected to correlate with imaging and RNA-seq results. The second goal is to clearly demonstrate the contribution of VCAM-1, as a gateway between systemic and brain inflammation by studying a mouse model of AD that cannot develop inflammation to blood vessels. In those animals, infection or a high-fat diet should not have an effect if VCAM-1 is, indeed, central to the propagation of inflammation to the brain. The third goal is to determine and visualize by imaging the beneficial effects of anti-inflammatory treatments and of the detrimental effects of systemic infection or of a high-fat diet. Ultimately, we expect this research will enable an earlier detection of processes leading to AD at a stage where it could be prevented or reversed.