Tau isoforms are differentially expressed across the hippocampus in chronic traumatic encephalopathy and Alzheimer\u2019s disease

Jonathan D Cherry,Ann C McKee,Victor E Alvarez,Zachary H Baucom,Thor D Stein,Yorghos Tripodis,Dennis W Dickson,Bertrand R Huber,Camille D Esnault

doi:10.1186/s40478-021-01189-4

Abstract

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease, characterized by hyperphosphorylated tau, found in individuals with a history of exposure to repetitive head impacts. While the neuropathologic hallmark of CTE is found in the cortex, hippocampal tau has proven to be an important neuropathologic feature to examine the extent of disease severity. However, the hippocampus is also heavily affected in many other tauopathies, such as Alzheimer’s disease (AD). How CTE and AD differentially affect the hippocampus is unclear. Using immunofluorescent analysis, a detailed histologic characterization of 3R and 4R tau isoforms and their differential accumulation in the temporal cortex in CTE and AD was performed. CTE and AD were both observed to contain mixed 3R and 4R tau isoforms, with 4R predominating in mild disease and 3R increasing proportionally as pathological severity increased. CTE demonstrated high levels of tau in hippocampal subfields CA2 and CA3 compared to CA1. There were also low levels of tau in the subiculum compared to CA1 in CTE. In contrast, AD had higher levels of tau in CA1 and subiculum compared to CA2/3. Direct comparison of the tau burden between AD and CTE demonstrated that CTE had higher tau densities in CA4 and CA2/3, while AD had elevated tau in the subiculum. Amyloid beta pathology did not contribute to tau isoform levels. Finally, it was demonstrated that higher levels of 3R tau correlated to more severe extracellular tau (ghost tangles) pathology. These findings suggest that mixed 3R/4R tauopathies begin as 4R predominant then transition to 3R predominant as pathological severity increases and ghost tangles develop. Overall, this work demonstrates that the relative deposition of tau isoforms among hippocampal subfields can aid in differential diagnosis of AD and CTE, and might help improve specificity of biomarkers for in vivo diagnosis.

Highlights

Tau is a microtubule associated protein that under homeostatic conditions, facilitates axonal transport and supports microtubule stability [28, 42]
Tau was found in different densities and distributions within hippocampal subfields in each disease To determine if specific hippocampal subregions had preferential accumulation of tau and if those increases are altered across disease, the hippocampus was subdivided into 4 fields (CA4, CA2/3, CA1, and the Subiculum), and tau isoform counts were performed (Fig. 1)
Overall, it was observed that there was a high level of tau pathology diversity between Alzheimer’s disease (AD) and Chronic traumatic encephalopathy (CTE) when examining within the medial temporal lobe

Summary

Introduction

Tau is a microtubule associated protein that under homeostatic conditions, facilitates axonal transport and supports microtubule stability [28, 42]. The microtubule-associated protein tau (MAPT) gene produces six different isoforms of tau through alternative splicing of pre-mRNA of exon 2, 3, and 10 [3]. Tauopathies demonstrate differential expression in the pathological aggregates of either 3R or 4R tau and help further define some diseases. Disease such as PSP and CBD primarily express 4R tau, while Pick’s disease express 3R tau [4]. 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]. 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]

Methods

Results

Conclusion