Grant: Project Grant

IL-17 is a molecule involved in inflammation and abundant in the plasma of Alzheimer's disease (AD) patients and animal models of AD. A key role for cerebrovascular dysfunction in the onset and progression of AD is increasingly recognized and we recently demonstrated that IL-17 exerts detrimental effects on cerebral circulation. However, the mechanisms by which IL-17 alters cerebral blood flow and whether IL-17 is involved in impaired cerebral blood flow regulation in AD remains to be investigated. More precisely, IL17 impairs the increase in cerebral blood flow produced by neural activity (neurovascular coupling), a critical mechanism that matches substrate delivery with energy demands in brain. Because impaired neurovascular coupling increases the vulnerability of the brain to stroke and neurodegenerative diseases, it is important to understand how changes in vascular tone in response to neural activity may be altered. Our preliminary data showed that antiinflammatory therapy, including immune cell therapy, normalizes neurovascular coupling in a model of hypertension. These data are very exciting since there are very few studies that aimed at studying the effects of the immune system on cerebral blood flow. Accordingly, the major objective of this research program is to study the role of inflammation on neurovascular coupling impairment observed in AD. We will test therapies targeting IL17 on cerebral blood flow, molecular characteristics of AD and cognition in a murine model of AD. These studies will be conducted in mice in vivo and in vitro using genetic, biochemical, anatomical and pharmacological approaches. These studies will improve our understanding of the mechanisms underlying linking vascular risk factors, neuroinflammation and AD. This may provide further therapeutic targets to reduce premature disability and death from dysfunctional cerebral blood flow.