Alzheimer’s disease brain contains tau fractions with differential prion-like activities

Abstract

Neurofibrillary tangles (NFTs) made of abnormally hyperphosphorylated tau are a hallmark of Alzheimer’s disease (AD) and related tauopathies. Regional distribution of NFTs is associated with the progression of the disease and has been proposed to be a result of prion-like propagation of misfolded tau. Tau in AD brain is heterogenous and presents in various forms. In the present study, we prepared different tau fractions by sedimentation combined with sarkosyl solubility from AD brains and analyzed their biochemical and pathological properties. We found that tau in oligomeric fraction (O-tau), sarkosyl-insoluble fractions 1 and 2 (SI1-tau and SI2-tau) and monomeric heat-stable fraction (HS-tau) showed differences in truncation, hyperphosphorylation, and resistance to proteinase K. O-tau, SI1-tau, and SI2-tau, but not HS-tau, were hyperphosphorylated at multiple sites and contained SDS- and β-mercaptoethanol–resistant high molecular weight aggregates, which lacked the N-terminal portion of tau. O-tau and SI2-tau displayed more truncation and less hyperphosphorylation than SI1-tau. Resistance to proteinase K was increased from O-tau to SI1-tau to SI2-tau. O-tau and SI1-tau, but not SI2-tau or HS-tau, captured tau from cell lysates and seeded tau aggregation in cultured cells. Heat treatment could not kill the prion-like activity of O-tau to capture normal tau. Hippocampal injection of O-tau into 18-month-old FVB mice induced significant tau aggregation in both ipsilateral and contralateral hippocampi, but SI1-tau only induced tau pathology in the ipsilateral hippocampus, and SI2-tau and HS-tau failed to induce any detectable tau aggregation. These findings suggest that O-tau and SI1-tau have prion-like activities and may serve as seeds to recruit tau and template tau to aggregate, resulting in the propagation of tau pathology. Heterogeneity of tau pathology within AD brain results in different fractions with different biological and prion-like properties, which may pose a major challenge in targeting tau for development of effective therapeutic treatments.

Tau in Health and Neurodegenerative Diseases

“…Oligomeric tau and PHF-tau isolated from AD brains can serve as prion-like seeds to induce the aggregation of normal tau both in vitro and in vivo, while monomeric heat-stable and straight filament (SF)-tau showed limited prion-like properties. However, AD O-tau is the most potent toxic species to induce pathological tau aggregation and propagation in vivo [80,96,[115][116][117].…”

“…For example, both the structures of PHF and SF in AD contain eight β-sheets in a C-shaped fold, but the intermolecular organization between the two kinds of protofilament is different [119]. PHF-tau, but not SF-tau, dramatically seeds tau aggregation in vitro and triggers the propagation of tau pathology in vivo [116]. Furthermore, the induced pathology in specific cell types is related to the origin of tau species.…”

Tau Seeding Mouse Models with Patient Brain-Derived Aggregates

“…Moreover, growing evidence suggests that this spread occurs via transmission of pathological tau from a donor cell to a recipient cell, such that recruitment of physiological tau in the latter generates new deleterious seeds. This pathological spread provides a good explanation for the stereotypical progression pattern of tau pathology observed in tauopathies [ 2 , 10 , 11 , 13 , 59 ].…”

“…These experiments consistently showed that soluble phosphorylated high molecular weight tau were the species involved in tau uptake and propagation [ 51 ]. However, oligomeric and sarkosyl-insoluble aggregated tau fractions isolated from human AD brains were also identified as seeds capable of inducing aggregation and pathological spread [ 59 ]. The precise nature of the tau species relevant for seeding and propagation is therefore still under investigation and may differ among individual AD patients [ 140 ].…”

Host Tau Genotype Specifically Regulates and Designs Tau Seeding and Spreading Following Intracerebral Injection of Identical Tau AD Inoculum

“…Several tau fractions in AD have differential prion-like activities [4]. Following this line of thinking, the diversity of tau strains may contribute to clinical diversity in AD [52,53]. As a working hypothesis, it may be postulated that variable composition of 3Rtau and 4Rtau isoforms is expressed in different brain regions and in different neurons in a particular individual.…”