Inflammation and Renin-Angiotensin System Dysfunction as Risk Factors for AD

We hypothesize that systemic disorders such as obesity and hypertension increase the risk for acquiring Alzheimer’s-type dementia through generation of a systemic immune/inflammatory response that, in turn, triggers glial activation and neuroinflammation. Central to this hypothesis are increases in levels of circulating cytokines—in particular soluble TNF, which increases BBB permeability and triggers chronic activation of brain resident microglia— as well as changes in the renin angiotensin system, which regulates blood pressure both inside and outside the CNS. Our overarching hypothesis will be tested in a common mouse model of Alzheimer’s disease (i.e. 5xFAD mice) exposed to a high-fat diet (to induce obesity/metabolic syndrome) or to angiotensin II (to induce hypertension). Signs of chronic systemic inflammation, BBB permeability, and immune cell trafficking into the CNS will be investigated in Dr. Tansey’s laboratories at Emory University. Changes in cognition and hippocampal synaptic physiology will be investigated by Dr. Norris’ group at the University of Kentucky. We expect that high fat diet and angiotensin will cause systemic inflammation and trafficking of immune cells into the CNS leading to impaired cognitive and synaptic function. We predict that these effects will be inhibited by a novel TNF inhibitor, XPro1595.