Summary Alzheimer's disease (AD) is the most common cause of dementia in the elderly and a majority of AD cases is sporadic without known causes. While the etiology of AD is multifactorial and complex, growing evidence suggests that traumatic brain injury (TBI) is a risk factor for development of AD and dementia. Repetitive TBI causes chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disease. Pathological TDP- 43 inclusions are one of the important hallmarks of neuropathology in CTE. Clinical studies reveal that a significant number of AD patients with various pathological subtypes display pathological TDP-43 inclusions. These similarities and overlap in neuropathology between CTE and AD suggest that CTE is a TBI-triggered AD- like neurodegenerative disease. TDP-43 is a DNA and RNA binding protein shuttled between the cytoplasm and the nucleus that regulates nuclear transcription, RNA splicing, and metabolism. However, our understanding of TDP-43 in AD neuropathology is still limited. In particular, it is not clear whether there are a linkage or interactions between TDP-43 aggregation and Aβ formation or p-tau and how TBI induces excessive TDP-43 expression, resulting in its aggregation and mislocalization. Our previous studies demonstrate that repetitive mild closed head injury (mCHI) in mice results in AD-like neuropathological changes, including robust TDP-43 production and p-tau. Importantly, our preliminary results show that a single mCHI accelerated accumulation of Aβ plaques and gliosis and increased production of TDP-43 and p-tau in APP transgenic (TG) mice, suggesting that TBI accelerates and exacerbates AD neuropathology and promotes progression. Particularly, we observed that knockdown of TDP-43 by shRNA silencing prevented repetitive mCHI-induced p-tau and downregulation of glutamate receptor subunits. Thus, we hypothesize that TBI-induced excessive expression of TDP-43 is an important mechanism of the pathogenesis and neuropathology in AD. In specific aim 1, we will test the prediction that a single mCHI accelerates or exacerbates neuropathological changes in APP transgenic mice; in specific aim 2, we will test the hypothesis that TDP-43 overproduction is a key factor in TBI-induced acceleration and progression of AD neuropathology as well as synaptic and cognitive declines, and in specific aim 3, we will test the prediction that neuroinflammation triggered by TBI stimulates TDP-43 transcription and expression via the NF-κB signaling pathway. The outcome of the proposed application will reveal a previously undefined mechanism by which abnormal overproduction of TDP-43 induced by TBI contributes to AD neuropathology and will provide experimental evidence that TDP-43 may be a therapeutic target for preventing development of TBI- associated AD neuropathology and dementia or for halting disease progression.