Abstract Text: Traumatic brain injury (TBI) is a known risk factor for the later development of Alzheimer’s disease (AD). Unfortunately, there are no therapies to ‘cure’ TBI or AD, and any drugs to improve symptoms have numerous side-effects. Therefore, new pharmacotherapies without side-effects are urgently needed. A major inflammatory cytokine upregulated following TBI and involved in AD pathology is Tumor Necrosis Factor (TNF). The transmembrane form of TNF (tmTNF) preferentially binds TNFR2 promoting predominantly beneficial outcomes (blocking its activity may cause immunological and cardiac dysfunction), while the soluble form of TNF (solTNF) preferentially binds TNFR1 promoting detrimental brain outcomes, including neuronal cell death, amyloid beta plaque and tau neurofibrillary tangle pathology. While traditional TNF inhibitors are non-selective at blocking TNFR1 and TNFR2 activity, a novel second-generation TNF inhibitor (XPro1595, INmuneBio Inc) selectively inhibits only solTNF/TNFR1 activity. In a clinical trial in cancer patients XPro1595 was safe and well-tolerated, and in a second clinical trial in AD patient’s interim data shows XPro1595 reverses brain WM neuroinflammatory levels. While TBI accelerates the onset of AD, the role of solTNF/TNFR1 activity in TBI-induced AD pathology has remained unknown. AD transgenic mice (3xTg-AD) underwent TBI (CCI injury model), treated with XPro1595 (10 mg/kg, S.C.) 30 minutes post-injury, and allowed to survive for 24 hours. Our data suggests XPro1595 treatment prevents injury-induced increases in glial reactivity (GFAP), APP and amyloid beta (6E10), Tau (Tau46), and phospho-Tau (AT8 and PHF-1) expression. This data supports the use of XPro1595 clinically following TBI to prevent the later development of AD pathology.
