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Bergold, Peter
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Spring 2024
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2024-03-25
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Abstract
Traumatic brain injury (TBI) is a leading cause of death and disability in the United States
and increases the risk of neurodegenerative diseases and dementia [4, 5]. There are no
treatments available to prevent neurodegeneration after TBI. Hyperphosphorylation of the
microtubule-associated protein tau (pTau) is a key feature of neurodegeneration triggered
by TBI. The tau gene can be alternatively spliced to generate tau with 3 or 4 repeated
microtubule-binding sequences (3R and 4R). Adult mice express only 4R tau, while the
adult human brain expresses 3R and 4R tau. This raises the possibility that tau isoform
expression may influence chronic closed-head injury pathophysiology. The central
hypothesis of this work is that tau isoform expression modulates neurodegeneration
following a single closed-head injury. Two specific aims (SA) test this hypothesis. SA1:
What is the time course and distribution of pathological protein aggregates after a
single moderate closed-head injury? SA2: Does the expression of 3R tau aggravate
the development of pathological protein aggregates and memory deficits after a
single moderate closed-head injury? The studies in this work show that a single closedhead
injury initially induces pTau+ cells and memory deficits in wild-type (WT) mice, which
chronically develop protein aggregates in the thalamus. In contrast, MAPTKI mice
expressing both 3R and 4R tau initially have a greater density of pTau+ cells but no
memory deficits. However, chronically injured MAPTKI mice have more protein
aggregates in the corpus callosum than WT mice and develop chronic spatial memory
deficits. These data suggest that a single TBI in the context of 3R tau may drive a more
severe early tauopathy that develops into chronic protein aggregate accumulation with
functional deficits. Further evaluation of this model could identify targets for treating
neurodegenerative diseases and dementia after TBI.
Citation
Furhang, R (2024). The Role of Tau Isoforms in Sub-Acute and Chronic Closed Head Injury [Doctoral dissertation, SUNY Downstate Health Sciences University]. SUNY Open Access Repository. https://soar.suny.edu/handle/20.500.12648/14824