TRAUMATIC BRAIN INJURY AND ALZHEIMER'S DISEASE
Alzheimer's disease (AD) is the most common cause of dementia in the elderly and a majority of AD cases issporadic without known causes. While the etiology of AD is multifactorial and complex, growing evidencesuggests that traumatic brain injury (TBI) is a risk factor for development of AD and dementia. Repetitive TBIcauses 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 asignificant 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 andthe nucleus that regulates nuclear transcription, RNA splicing, and metabolism. However, our understanding ofTDP-43 in AD neuropathology is still limited. In particular, it is not clear whether there are a linkage or interactionsbetween TDP-43 aggregation and A? 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 closedhead injury (mCHI) in mice results in AD-like neuropathological changes, including robust TDP-43 productionand p-tau. Importantly, our preliminary results show that a single mCHI accelerated accumulation of A? plaquesand gliosis and increased production of TDP-43 and p-tau in APP transgenic (TG) mice, suggesting that TBIaccelerates and exacerbates AD neuropathology and promotes progression. Particularly, we observed thatknockdown of TDP-43 by shRNA silencing prevented repetitive mCHI-induced p-tau and downregulation ofglutamate receptor subunits. Thus, we hypothesize that TBI-induced excessive expression of TDP-43 is animportant mechanism of the pathogenesis and neuropathology in AD. In specific aim 1, we will test the predictionthat a single mCHI accelerates or exacerbates neuropathological changes in APP transgenic mice; in specificaim 2, we will test the hypothesis that TDP-43 overproduction is a key factor in TBI-induced acceleration andprogression of AD neuropathology as well as synaptic and cognitive declines, and in specific aim 3, we will testthe prediction that neuroinflammation triggered by TBI stimulates TDP-43 transcription and expression via theNF-?B signaling pathway. The outcome of the proposed application will reveal a previously undefinedmechanism by which abnormal overproduction of TDP-43 induced by TBI contributes to AD neuropathology andwill 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.