The Role of Tau Isoforms in Sub-Acute and Chronic Closed Head Injury

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.