Tau isoform profile and phosphorylation state in dementia pugilistica recapitulate Alzheimer's disease

Insights into mechanisms of familial Alzheimer's disease (AD) caused by gen etic mutations have emerged rapidly compared to sporadic AD. Indeed, despit e identification of several sporadic AD risk factors, it remains enigmatic how or why they predispose to neurodegenerative disease. For example, traum atic brain injury (TBI) predisposes to AD, and recurrent TBI in career boxe rs may cause a progressive memory disorder associated with AD-like brain pa thology known as dementia pugilistica (DP). Although the reasons for this a re unknown, repeated TBI may cause DP by mechanisms similar to those involv ed in AD. To investigate this possibility, we compared the molecular profil e of tau pathologies in DP with those in AD and showed that the same tau ep itopes map to filamentous tau inclusions in AD and DP brains, while the abn ormal tau proteins isolated from DP brains are indistinguishable from the s ix abnormally phosphorylated brain tau isoforms in AD brains. Thus, these d ata suggest that recurrent TBI may cause DP by activating pathological mech anisms similar to those that cause brain degeneration due to accumulations of filamentous tau lesions in AD, and similar, albeit attenuated, activatio n of these processes by a single TBI may increase susceptibility to sporadi c AD decades after the event.