Facilitated By

San Antonio Medical Foundation


UT Health San Antonio

The UT Health San Antonio, with missions of teaching, research and healing, is one of the country’s leading health sciences universities.

Principal Investigator(s)
Chen, Chu
Funded by
Research Start Date

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.

Collaborative Project
Basic Research