Tau Pathology in Chronic Traumatic Encephalopathy and Alzheimer's Disease: Similarities and Differences

Abstract

Traumatic brain injury (TBI) has been associated with the development of Alzheimer's disease (AD) because these conditions share common pathological hallmarks: amyloid-β and hyperphosphorylated tau accumulation. However, given recent data it is uncertain if a history of TBI leads to the development of AD. Moreover, chronic traumatic encephalopathy (CTE), caused by repetitive mild TBI and characterized by progressive neurodegeneration with hyperphosphorylated tau, has come to be recognized as distinct from AD. Therefore, it is important to elucidate the clinical outcomes and molecular mechanisms underlying tau pathology following TBI. We summarize the histopathological features and clinical course of TBI in CTE, comparing the tau pathology with that in AD. Following brain injury, diffuse axonal injury, and hyperphosphorylated tau aggregates are observed within a shorter period than in AD. Hyperphosphorylated tau deposition usually begins in the perivascular area of the sulci in the cerebral cortex, then spreads unevenly in the cortex in CTE, while AD shows diffuse distribution of hyperphosphorylated tau in the cortical areas. We also highlight the molecular profile of tau and the implications of tau progression throughout the brain in both diseases. Tau contains phosphorylation sites common to both conditions. In particular, phosphorylation at Thr²³¹ triggers a conformational change to the toxic cis form of tau, which is suggested to drive neurodegeneration. Although the mechanism of rapid tau accumulation remains unknown, the structural diversity of tau might result in these different outcomes. Finally, future perspectives on CTE in terms of tau reduction are discussed.

Keywords: chronic traumatic encephalopathy; cis p-tau; prion; tau; traumatic brain injury.

Figure 1

Formation of hyperphosphorylated tau aggregates. Under normal condition, the microtubule-associated protein tau is soluble and abundant in axons of neurons. In pathological conditions, tau can be hyperphosphorylated and dissociates from microtubules. Then hyperphosphorylated tau translocates to the cell body and aggregates into intracellular inclusions termed paired helical filaments (PHFs) and neurofibrillary tangles (NFTs). (B) Tau isoforms. There are six isoforms of tau in human brain. Tau isoforms with four microtubule binding domains, designated as 4R-tau, are accumulated in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), whereas tau isoforms with three microtubule binding domains, designated as 3R-tau, are observed in Pick's disease. All six tau isoforms are involved in AD. This pattern is also detected in Down syndrome (DS), and amyotrophic lateral sclerosis and parkinsonism-dementia complex of Guam syndrome (ALS/PDC), and chronic traumatic encephalopathy (CTE) following TBI. (C) Characteristic pathology in AD and CTE. Upper panels: AD brains show diffuse cortical distribution of neurofibrillary tangles, preferentially distributed in laminae III and V without accentuation deep within sulci. Few fibrillary tangles exist around the small vessels. Double immunostaining demonstrates the coexsistence of abundant amyloid-β plaques (red) and interspersed PHF-1 neurofibrillary tangles (brown). Lower panels: In CTE, AT8 staining exhibits irregular cortical distribution of p-tau pathology with prominent subpial clusters of p-tau astrocytic tangles, focal accumulation deep within sulci, and neurofibrillary tangles in superficial cortical laminae II–III. Perivascular distribution of astrocytic tangles and neurofibrillary tangles are prominent in the small vessels. Double immunostaining reveals dense neurofibrillary tangles (brown) without amyloid-β plaques (red). Reproduced with permission from McKee et al. (8). (D) Representative tau phosphorylation sites in AD and CTE. CTE shares common phosphorylation sites with AD. Phosphorylation of tau at Thr²³¹ enables the cis-trans conformational change of p-tau Cis and the trans formation of phosphorylated tau. Trans formation of p-tau, observed in healthy subjects, promotes microtubule assembly, and is critical for normal neuronal function. Phosphorylation status is unstable and easy to be dephosphorylated. Cis p-tau is stable and resistant to binding to microtubules, protein phosphatases, and degradation. In AD and TBI, cis p-tau is robustly accumulated and thereby causes and spreads tau aggregation, contributing to the development of neurodegeneration.