Kevin Wang, Ph.D

A biochemical Link Between Traumatic Brain Injury and Alzheimer's Disease

Existing evidence suggests that traumatic brain injury (TBI) is a risk factor for developing Alzheimer's disease (AD) later in life. However, the biochemical linkage between these two diseases is currently undefined. We propose here that TBI-mediated aberrant tau cross linking and aggregation might trigger the initiation of AD pathology in TBI cases. Recent studies have demonstrated that tau is a potential substrate of the calcium-dependent protein cross-linking enzyme, transglutaminase-2 (TG-2), and induction of TG-2 expression and activity in the brain was observed in AD patients when compared to healthy subjects. Our own recent studies have shown sustained induction of TG-2 after experimental TBI.

We propose that TG-2 might be the missing biochemical link between TBI and AD. Our hypothesis is that TBI-induced TG-2 expression and activation may increase tau protein cross-linking and these aggregated tau molecules may become seeds for further homophilic deposition, ultimately over extended period of time leading to neurofibrillary tangle (NFT) formation and clinical manifestation of AD. In this proposed study, induction of TG-2 protein expression and activity after TB1 will be determined at different injury magnitudes and time points for a period of 2 months using a rat model of control cortical impact. Identification of tau isoform(s) vulnerable to TG-2 cross-linking will thereby be a necessary step in unraveling the molecular pathogenesis of NFTs.