Modulation of peripheral inflammation and immune cell traffic in AD by XPro1595

We hypothesize that the age-dependent dysregulation of complex immune/CNS interactions accelerates and/or exacerbates pathophysiologic processes involved in AD and related disorders. Central to this hypothesis are age-related increases in levels of circulating cytokines, in particular soluble TNF, which increase BBB permeability and trigger chronic activation of brain resident microglia. To test this, we will induce chronic systemic inflammation to increase circulating levels of cytokines. We expect to see (1) increased immune cell traffic to the CNS, (2) enhanced neuroinflammation, (3) greater cognitive decline, and (4) exacerbated amyloid pathology in 5xFAD mice compared to age-matched non-Tg mice and untreated 5xFAD mice. Acutely dissociated brain slices prepared by Dr. Norris (U Kentucky) will assess hippocampal synaptic function and plasticity. We expect (1) reduced CA3-CA1 synaptic strength, (2) reduced LTP, and enhanced LTD in inflammed vs. non-inflammed 5xFAD and non-Tg mice. The novel TNF inhibitor XPro1595 will be tested for efficacy in preventing adverse effects of chronic peripheral inflammation as well as progressive amyloid pathology.