TBI is the 3rd greatest risk factor for developing AD, behind genetics and aging. TBI is associated with a 3-4 year earlier onset of cognitive impairment, and increased cortical thinning and amyloid plaques in people with AD. The underlying mechanisms of this relationship are not understood, and as a result there are no treatments that protect patients from accelerated AD after TBI. We reported that tau is pathologically acetylated after TBI. Acetylated tau is significantly more elevated in the brains of human AD subjects with a history of TBI, compared to AD alone and healthy controls. Therefore, we hypothesized that early tau acetylation after TBI is mechanistically involved in the acceleration of AD. We developed a mouse model of TBI-mediated acceleration of AD-like pathology and cognitive impairment in 5xFAD mice. Our unique blast mediated multimodal TBI model is reproducible and clinically relevant. 8-week-old male and female 5xFAD and WT littermates underwent sham/TBI and were assessed after two weeks via Morris water maze, immunohistochemistry, western blot, and single nuclear RNA sequencing. For treatment studies, the FDA-approved non-steroidal inflammatory drug diflunisal, which inhibits the p300-CBP acetyltransferase enzyme that acetylates tau, or vehicle was initiated 24 hours after TBI and continued daily. To investigate potential mechanisms, we developed an in vitro TBI model with Hela cells that stably express amyloid precursor protein or tau. TBI causes learning deficits in young 5xFAD mice that do not occur in sham 5xFAD mice or in TBI-injured WT littermates. TBI accelerates amyloid plaques in 5xFAD mice. 5xFAD mice show greater elevation of acetylated tau after TBI, compared to WT mice. Hippocampal snRNA sequencing showed that TBI or 5xFAD mutations alone primarily perturb neurons. By contrast, TBI in 5xFAD mice drastically alters transcription in multiple cell types. Diflunisal treatment reduces acetylated-tau and rescues behavior deficits after TBI in 5xFAD mice. Amyloid precursor protein and tau expressing cells are more susceptible to in vitro TBI, compared to wild type cells. TBI accelerates onset of AD-like pathologies in 5xFAD mice. Preliminary evidence shows that pharmacologically reducing acetylated tau rescues TBI-induced cognitive deficits in 5xFAD mice.

Traumatic brain injury (TBI) is the leading cause of death in young people and can cause cognitive and motor dysfunction and disruptions in functional connectivity between brain regions. In human TBI patients and rodent models of TBI, functional connectivity is decreased after injury. Recovery of connectivity after TBI is associated with improved cognition and memory, suggesting an important link between connectivity and functional outcome. We examined widespread alterations in functional connectivity following TBI using simultaneous widefield mesoscale GCaMP7c calcium imaging and electrocorticography (ECoG) in mice injured using the controlled cortical impact (CCI) model of TBI. Combining CCI with widefield cortical imaging provides us with unprecedented access to characterize network connectivity changes throughout the entire injured cortex over time. Our data demonstrate that CCI profoundly disrupts functional connectivity immediately after injury, followed by partial recovery over 3 weeks. Examining discrete periods of locomotion and stillness reveals that CCI alters functional connectivity and reduces theta power only during periods of behavioral stillness. Together, these findings demonstrate that TBI causes dynamic, behavioral state-dependent changes in functional connectivity and ECoG activity across the cortex.

Traumatic brain injury (TBI) afflicts 70 million people worldwide annually and is the 3rd overall risk factor for developing Alzheimer's disease (AD), behind genetics and aging. In patients with AD, a history of TBI is associated with a 3-4 year earlier onset of cognitive impairment. TBI and AD share many pathologies, including blood brain barrier dysfunction, neuroinflammation, and protein aggregation. Yet, the underlying mechanism of this relationship is not understood, and there are no treatments that protect patients from accelerated AD after TBI. We recently reported that tau, a microtubule binding protein essential for neuronal health, is acetylated after TBI. Acetylation impairs tau binding to microtubules, leading to its mis-localization into the cell soma and pathological aggregation. Acetylated tau is also elevated early in AD, and acetylated tau was significantly more elevated in the brains of human AD subjects with a history of TBI, compared to AD alone and healthy controls. Therefore, we hypothesize that TBI-induced tau acetylation drives the acceleration of AD. To study this phenomenon, we developed a mouse model of TBI that accelerates AD-like pathology and cognitive impairment in 5xFAD mice, and amyloid-driven AD model. Our unique model of multimodal TBI produces a complex and reproducible brain injury with neurodegeneration and neurobehavioral impairment, beginning with acute axonal degeneration and persisting chronically with blood-brain barrier degradation and nerve cell death. This model of TBI also produces the same systemic metabolic alterations that are reported in TBI patients. TBI causes learning deficits in young 5xFAD mice that are not seen in either sham-injured 5xFAD mice or in wild type littermates subjected to TBI. TBI also accelerates amyloid deposition in 5xFAD mice. We hypothesize that TBI will also worsen blood brain barrier function in 5xFAD mice. Importantly, 5xFAD mice show greater elevation of acetylated tau after TBI, compared to WT mice. Preliminary data suggests that treatment with the FDA-approved non-steroidal inflammatory drug diflunisal, which inhibits the enzyme that acetylates tau, reduces acetylated tau and rescues behavior deficits after TBI in 5xFAD mice.