Oligomeric, phosphorylated, and truncated tau and spliceosome pathology within the entorhinal–hippocampal connectome across stages of Alzheimer's disease

• Published in: Journal of comparative neurology (1911) Vol. 531; no. 18; pp. 2080 - 2108
• Main Authors: Mahady, Laura J., Perez, Sylvia E., Malek‐Ahmadi, Michael, Mufson, Elliott J.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-12-2023
• Subjects: Alternative splicing; Alzheimer Disease - pathology; Alzheimer's disease; Ammon's horn; Cognitive ability; Connectome; Cortex (entorhinal); Dentate gyrus; Epitopes; Hippocampus; Hippocampus - metabolism; Humans; Immunohistochemistry; medial temporal lobe; mild cognitive impairment; Neurodegenerative diseases; Neurofibrillary tangles; Neurofibrillary Tangles - pathology; Pathology; propagation; Spliceosomes - metabolism; Spliceosomes - pathology; splicing; Subiculum; tau; Tau protein; tau Proteins - metabolism; Temporal cortex; Temporal lobe; medial temporal lobe; propagation; neurofibrillary tangles; tau; mild cognitive impairment; splicing; Alzheimer's disease
• ISSN: 0021-9967; 1096-9861; 1096-9861
• DOI: 10.1002/cne.25466

Neurofibrillary tangles (NFTs) contain abnormally phosphorylated tau proteins, which spread within components of the medial temporal lobe (MTL) memory circuit in Alzheimer's disease (AD). Here, we used quantitative immunohistochemistry to determine the density of posttranslational oligomeric (TOC1 and TNT1), phosphorylated (AT8), and late truncated (TauC3) tau epitopes within the MTL subfields including entorhinal cortex (EC) layer II, subiculum, Cornu Ammonis (CA) subfields, and dentate gyrus (DG) in subjects who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD. We also examined whether alterations of the nuclear alternative splicing protein, SRSF2, are associated with tau pathology. Although a significant increase in TOC1, TNT1, and AT8 neuron density occurred in the EC in MCI and AD, subicular, DG granule cell, and CA1 and CA3 densities were only significantly higher in AD. TauC3 counts were not different between connectome regions and clinical groups. SRSF2 intensity in AT8‐positive cells decreased significantly in all regions independent of the clinical groups examined. CA1 and subicular AT8, TauC3, and oligomeric densities correlated across clinical groups. EC AT8 counts correlated with CA subfields and subicular and DG values across clinical groups. Oligomeric and AT8 CA1, EC, and subicular density correlated with Braak stage. Decreased nuclear SRSF2 in the presence of cytoplasmic phosphorylated tau suggests a dual‐hit process in NFT formation within the entorhinal hippocampal connectome during the onset of AD. Although oligomeric and phosphorylated tau follow a stereotypical pattern, clinical disease stage determined density of tau deposition and not anatomic location within the entorhinal–hippocampal connectome.
In this study, we determined the density of posttranslational oligomeric, phosphorylated, and late truncated tau epitopes within medial temporal lobe (MTL) subfields including entorhinal cortex (EC) layer II, subiculum, Cornu Ammonis (CA) subfields, and dentate gyrus (DG) in subjects who died with a clinical diagnosis of no cognitive impairment, mild cognitive impairment (MCI), and Alzheimeŕs disease (AD). We also examined whether alterations of the nuclear alternative splicing protein, SRSF2, are associated with tau pathology. Our results suggest a dual‐hit process in NFT formation, with decreased nuclear SRSF2 in the presence of cytoplasmic phosphorylated within the entorhinal hippocampal connectome during the onset of AD. Although oligomeric and phosphorylated tau follow a stereotypical pattern, clinical disease stage determined density of tau deposition and not anatomic location within the entorhinal‐hippocampal connectome.