Evolution of neuronal and glial tau isoforms in chronic traumatic encephalopathy

Abstract

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy characterized by accumulation of hyperphosphorylated tau (p‐tau) in perivascular aggregates in neurons and glia at the depths of neocortical sulci and progresses to diffuse neocortical, allocortical and brainstem structures. The strongest risk factor is exposure to repetitive head impacts acquired most commonly through contact sports and military service. Given that CTE can only be definitively diagnosed after death, a better understanding of the cellular and molecular changes in CTE brains may lead to identification of mechanisms that could be used for novel biomarkers, monitoring progression or therapeutic development. Disruption of alternative pre‐mRNA splicing of tau mRNA plays a pathogenic role in tauopathy, with multiple characteristic patterns of isoform accumulation varying among tauopathies. Limited data are available on CTE, particularly at early stages. Using biochemical and histological approaches, we performed a detailed characterization of tau isoform signatures in post‐mortem human brain tissue from individuals with a range of CTE stages (n = 99). In immunoblot analyses, severity was associated with decreased total monomeric tau and increased total oligomeric tau. Immunoblot with isoform‐specific antisera revealed that oligomeric tau with three and four microtubule binding domain repeats (3R and 4R) also increased with CTE severity. Similarly, immunohistochemical studies revealed p‐tau accumulation consisting of both 3R and 4R in perivascular lesions. When the ratio of 4R:3R was analyzed, there was mixed expression throughout CTE stages, although 4R predominated in early CTE stages (I‐II), a 3R shift was observed in later stages (III‐IV). While neurons were found to contain both 3R and 4R, astrocytes only contained 4R. These 4R‐positive cells were exclusively neuronal at early stages. Overall, these findings demonstrate that CTE is a mixed 4R/3R tauopathy. Furthermore, histologic analysis reveals a progressive shift in tau isoforms that correlates with CTE stage and extent of neuronal pathology.

Tau isoforms are differentially expressed across the hippocampus in chronic traumatic encephalopathy and Alzheimer’s disease

“…Disease such as PSP and CBD primarily express 4R tau, while Pick’s disease express 3R tau [ 4 ]. AD, CTE and PART have all been found to express both 3R and 4R tau [ 8 , 9 , 37 ]. However, the isoform expression might be dynamic and change over the course of disease.…”

“…However, the isoform expression might be dynamic and change over the course of disease. In CTE, early pathology was observed to express more 4R tau while later, more severe pathology had equal or higher levels of 3R tau suggesting an evolution of isoform during the course of disease [ 8 ]. Similar evolution of tau has been suggested for AD as well [ 18 , 39 ].…”

“…Similar evolution of tau has been suggested for AD as well [ 18 , 39 ]. It was hypothesized that the elevated 3R density was correlated with the appearance of extracellular neurofibrillary tangle (NFT) pathology that was left behind after a neuron has died (ghost tangle) [ 8 , 38 ].…”

Space-occupying brain lesions, trauma-related tau astrogliopathy, and ARTAG: a report of two cases and a literature review

“…That is, the p-tau+ astrocytes expressed only 4R tau, similar to ARTAG-p-tau+ astrocytes, while neurons in CTE express both 3R and 4R tau, similar to AD [ 43 ]. Cherry et al [ 48 ] examined 99 cases of CTE–NC for the presence of 3R and 4R tau. Neurons expressed both 3R and 4R tau pathology, while astrocytes only expressed 4R tau pathology.…”

“…Intriguingly, p-tau+ astrocytes increased with age. A tipping point was seen in the sixth decade of life, with the percentage of p-tau+ astrocytes increasing linearly into the seventh and eight decade of life, at which point astrocytes accounted for at least 50% of the 4R tau+ cells in the perivascular lesions [ 48 ]. Many questions remain about the importance of intrinsic (including genetic) factors, injury physics, and the how idiosyncratic single-trauma (TBI) and multiple/repetitive trauma (CTE) conditions relate to these findings.…”