Chronic low-grade inflammation is often referred to as 'the silent killer' and has been strongly implicated as a risk factor in multiple neurodegenerative disorders, including Alzheimer's disease (AD). Moreover, it is well recognized that AD patients experience greater cognitive decline during periods of systemic infections. In this proposal, we investigate the impact of peripheral immune cell infiltration of brain tissue on the progression of AD-like pathology in a mouse model of the disease. Identification of the immune cell types present in AD-relevant regions during disease progression could provide critical new information on the complex interaction between the brain and the immune system taking place during aging and in AD and may reveal important clues to develop novel disease-modifying therapies to treat AD. Because our ultimate goal is to translate new knowledge about the role of the immune system and inflammation into disease-modifying therapies, we also seek to obtain pre-clinical in vivo proof of efficacy for a novel brain-permeant anti-TNF biologic with IND status, XPro1595. We will investigate its ability to lessen immune cell infiltration, neuroinflammation, and ameliorate the AD-like progressive phenotype in the 5xFAD mouse model of AD. Current FDA-approved TNF inhibitors prescribed for patients with rheumatoid arthritis and inflammatory bowel disease dampen one's ability to fight infection and have been linked to neurological defects and demyelinating disease in patients without prior neurological diagnosis. Therefore, the non-selective TNF inhibitors are not a suitable option when considering the treatment of neuroinflammatory neurodegenerative disease. Although our studies specifically focus on AD, our findings are expected to shed important new insight on immune-brain interactions and could have a major impact on other brain disorders where the BBB is compromised, including head trauma, Parkinson's disease, multiple sclerosis and many others.