Inhibition of Soluble TNF Mitigates Traumatic Brain Injury as a Risk Factor for the Development of Amyloidogenic Proteins and Functional Deficits in 3xTg-AD Mice.

Authors

Chelsie N Poffenberger, Michelle M Taylor, Katelyn Larson, Elliott J Mufson, Kirsty J Dixon

Published in

Journal of neurotrauma. Pages 8977151261469044. Jul 24, 2026. Epub Jul 24, 2026.

Abstract

Traumatic brain injury (TBI) is a well-known risk factor for dementia with Alzheimer's disease (AD), and there are no known therapies that can mitigate this risk. Pre-clinical studies demonstrate a temporary upregulation of amyloid beta (Aβ) and corresponding neurological dysfunction following TBI with little-to-no studies developing interventions to prevent this pathophysiology. The pro-inflammatory cytokine tumor necrosis factor (TNF) has been shown to promote the development of AD, and here we investigate whether a clinically relevant biologic known as XPro1595 that neutralizes soluble TNF (solTNF) can mitigate TBI as a risk factor for the development of amyloidogenic proteins and corresponding neurological dysfunction. Following a single controlled cortical impact model of TBI or sham-injury, adult male 3xTg-AD mice were treated acutely with either XPro1595, a dominant-negative protein that neutralizes soluble TNF (10 mg/kg, S.C.), or vehicle solution. Between 6 h and 1 month post-injury (MPI), levels of cytokines, inflammatory markers, and AD-related proteins were evaluated in the ipsilateral hippocampus. Additionally, animals were behaviorally tested for deficits in cognition (learning and memory), as well as hindpaw mechanical hypersensitivity. TBI induced a significant increase in TNF (ELISA, 6 h) and TNFR1 (Western blot, 3 days post-injury [DPI]) expression, which correlated with an increase in BACE1, Aβ₄₂, and caspase-3 at 3 and 7 DPI. Significant deficits in cognition and mechanical hypersensitivity were found at 7 DPI with similar trends at 1 MPI. In comparison, injured mice treated with XPro1595 had improvements in cognition and mechanical hypersensitivity (cf. vehicle-treated injured mice) and did not have these same increases in BACE1, Aβ₄₂, and caspase-3 (levels were similar to sham-injured mice), likely by increasing NF-κB deactivation (pNF-κB [p65; Ser468]), indicative of a reduced inflammatory response. Overall, treatment with XPro1595 following TBI prevented the development of amyloidogenic proteins and corresponding neurological dysfunction. Clinically, these data support the use of XPro1595 as a clinically relevant therapeutic for patients with TBI to mitigate the risk of increased Aβ levels and neurological decline subacutely post-injury.

PMID:
42498936
Bibliographic data and abstract were imported from PubMed on 25 Jul 2026.

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