Sleep disruption following traumatic brain injury generates early Alzheimer’s-related protein variant pathology in wild-type mice

Traumatic brain injury (TBI) is a major risk factor for Alzheimer’s disease and related dementias (ADRDs) due to sustained neuronal stress and impaired proteostasis. Pathological mechanisms linking TBI to ADRDs include the accumulation of toxic variants of amyloid-β (Aβ), tau, and TAR DNA-binding protein 43 (TDP-43). TBI is frequently accompanied by chronic sleep disturbances, which may exacerbate neurodegenerative vulnerability by increasing physiological stress and disrupting metabolic waste clearance. We hypothesized that acute stress induced by TBI, combined with separate longer term stress induced by post-injury sleep disruption, promotes the generation of ADRD-associated protein variants and contributes to behavioral dysfunction. Male and female C57BL/6J mice received mild TBI, moderate TBI, or sham injury using a midline fluid percussion model, followed by a 7-day recovery period and then 7 days of either continuous sleep disruption or no sleep disruption. Behavioral assessments were conducted through 14 days post-injury, and brain tissue was collected on day 15 for regional analysis using conformational variant-selective antibodies targeting disease-relevant forms of Aβ, tau, and TDP-43. TBI induced accumulation of ADRD-related protein variants in wild-type mouse brain similar to those observed in early-stage human AD tissue. Although most group-level behavioral deficits and protein pathology resolved by 14 days post-injury, sleep disruption altered recovery in a sex- and injury-dependent manner. A subset of mice displayed persistent behavioral impairments accompanied by elevated levels of toxic protein variants. Correlation analyses identified variant- and region-specific relationships with functional outcomes. Levels of specific Aβ and tau variants frequently associated with behavioral impairment, selected Aβ and tau variants also appeared to reflect an early, potentially adaptive response to stress. These findings demonstrate that TBI-induced stress is sufficient to generate early ADRD-like pathology in wild-type mice and that post-injury sleep disruption modifies this response in a sex-dependent manner, where females had increased accumulation of key AD-related Aβ and tau variants.