Traumatic brain injury-associated epigenetic changes and the risk for neurodegenerative diseases

Abstract

Epidemiological studies have shown that traumatic brain injury (TBI) increases the risk for developing neurodegenerative diseases (NDs). However, molecular mechanisms that underlie this risk are largely unidentified. TBI triggers widespread epigenetic modifications. Similarly, NDs such as Alzheimer’s or Parkinson’s are associated with numerous epigenetic changes. Although epigenetic changes can persist after TBI, it is unresolved if these modifications increase the risk of later ND development and/or dementia. We briefly review TBI-related epigenetic changes, and point out putative feedback loops that might contribute to long-term persistence of some modifications. We then focus on evidence suggesting persistent TBI-associated epigenetic changes may contribute to pathological processes (e.g., neuroinflammation) which may facilitate the development of specific NDs – Alzheimer’s disease, Parkinson’s disease, or chronic traumatic encephalopathy. Finally, we discuss possible directions for TBI therapies that may help prevent or delay development of NDs.

Chronic Traumatic Encephalopathy as the Course of Alzheimer’s Disease

“…However, the precise molecular pathways still need to be fully elucidated and require more research. While taking this approach, other NDs (such as Alzheimer's or Parkinson's Diseases (AD and PD)) are worth mentioning, as they are strongly connected with the epigenetic changes of the comprehensively described mechanisms [23,26]. The present data suggest that a TBI is a potent risk factor for these NDs (CTE, AD, and PD) due to, e.g., persistent neuroinflammation, but most theories are hypothetical theses [23].…”

“…These neuropathological findings can initially localize in mechanical trauma regions and then spread into the whole structure through an inflammatory response. The pathology of this process is exceptional, as these lesions are unlike any observed tauopathy [16,21,23,24] and will be precisely described in the subsequent paragraph.…”

“…From a molecular point of view, CTE is a tauopathy with progressive accumulation of the tau protein observed even in middle-aged patients (the first significant findings were made in American football players in 2005) [19,23,25]. The characteristic pathognomonic lesions of a perivascular accumulation of neuronal phosphorylated tau (p-Tau) are described.…”

“…Plenty of different groups of people are exposed to repetitive head impacts (RHIs), also known as repetitive traumatic brain injuries (TBIs), defined as cumulative exposure to recurrent concussive and subconcussive events. These injuries can be caused through contact and collision sports at any age, military service, severe epilepsy attacks, or being the victim of domestic violence [16,17,23,24].…”

“…While taking this approach, other NDs (such as Alzheimer's or Parkinson's Diseases (AD and PD)) are worth mentioning, as they are strongly connected with the epigenetic changes of the comprehensively described mechanisms [23,26]. The present data suggest that a TBI is a potent risk factor for these NDs (CTE, AD, and PD) due to, e.g., persistent neuroinflammation, but most theories are hypothetical theses [23]. In conclusion, TBIs are being considered a cause of significant preventable neurodegeneration [16].…”