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

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.

Nonlocal Models in the Analysis of Brain Neurodegenerative Protein Dynamics with Application to Alzheimer's Disease

“…After observing several characteristics of the models, we move to an interesting scenario in the brain network model where some regions in the brain satisfy the primary tauopathy, and the other regions satisfy the secondary tauopathy. This is called a mixed tauopathy, and it is more realistic than primary or secondary 38 . We also study the damage dynamics in each of the tauopathies.…”

NLRP1 Inflammasome Activation in the Hippocampal Formation in Alzheimer’s Disease: Correlation with Neuropathological Changes and Unbiasedly Estimated Neuronal Loss

“…In contrast to NLRP1, ASC, and cGSDMD, whose expression is highest in the CA2/3 region, CASP-6 immunostaining is, besides CA2/3, also high in the CA1 in the AD group. The CA1 field is known to have a higher tau pathology burden [ 77 , 78 , 79 ] so we propose that because NLRP1, ASC, and cGSDMD have lower expression in the CA1 than CASP-6, they could be more active at the beginning of the pathological process, inside neurons at the early stage of neurofibrillary changes. Further, CASP-6 would also be present in later stages of AD in neurons with mature tangles.…”

Inhibition of CK2 mitigates Alzheimer’s tau pathology by preventing NR2B synaptic mislocalization

“…Accordingly, these diseases may possess isoform-specific pathogenicity. In tauopathy patients, 3R tau correlates with increases in extracellular tau and a shift from 4R to 3R tau corresponds to disease severity [ 10 , 32 ]. Tau isoforms retain different microtubule binding properties that facilitate unique pathological roles [ 28 ].…”