Abstract
Alzheimer’s disease (AD) is characterized by accumulation of tau neurofibrillary tangles (NFTs) and, according to the prion model, transcellular propagation of pathological “seeds” may underlie its progression. Staging of NFT pathology with phospho-tau antibody is useful to classify AD and primary age-related tauopathy (PART) cases. The locus coeruleus (LC) shows the earliest phospho-tau signal, whereas other studies suggest that pathology begins in the transentorhinal/entorhinal cortices (TRE/EC). The relationship of tau seeding activity, phospho-tau pathology, and progression of neurodegeneration remains obscure. Consequently, we employed an established cellular biosensor assay to quantify tau seeding activity in fixed human tissue, in parallel with AT8 phospho-tau staining of immediately adjacent sections. We studied four brain regions from each of n = 247 individuals across a range of disease stages. We detected the earliest and most robust seeding activity in the TRE/EC. The LC did not uniformly exhibit seeding activity until later NFT stages. We also detected seeding activity in the superior temporal gyrus (STG) and primary visual cortex (VC) at stages before NFTs and/or AT8-immunopositivity were detectable. AD and putative PART cases exhibited similar patterns of seeding activity that anticipated histopathology across all NFT stages. Our findings are consistent with the prion model and suggest that pathological seeding activity begins in the TRE/EC rather than in the LC. In the analysis of tauopathy, quantification of seeding activity may offer an important addition to classical histopathology.
Highlights
Tauopathies constitute a diverse group of neurodegenerative diseases that include Alzheimer’s disease (AD)
We previously developed a protocol to compare seeding activity from fixed brain section punch biopsies in mice with AT8 immunostaining in adjacent tissue sections [29]
To verify the reliability of this method in the human brain, we compared seeding activity in two adjacent 4 mm punch biopsies taken from the combined transentorhinal/entorhinal cortices (TRE/entorhinal cortex (EC)) region in individual AD and putative primary age-related tauopathy (PART) fixed brain samples
Summary
Tauopathies constitute a diverse group of neurodegenerative diseases that include Alzheimer’s disease (AD). Recent work in vitro [17] and in vivo [10, 26, 28, 36, 38] indicates that in experimental systems tau assemblies (seeds) spread pathology between interconnected neurons and progressively trigger further aggregation of native tau This is similar to the pathophysiology of prion diseases, where prion protein (PrP) adopts a beta sheet-rich conformation that self-assembles and acts as a template to convert native PrP to a pathogenic form [35, 37]. We have previously developed a sensitive and specific cell-based “biosensor” assay to detect tau seeding activity in biological samples [18, 24] When we used this assay in a transgenic mouse model of tauopathy, we observed seeding activity far in advance of detectable histopathology or accumulation of insoluble tau protein [24]. We have assessed the relationship of seeding to phospho-tau pathology in the LC and in more distant cortical regions, thereby addressing fundamental questions about AD pathogenesis
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