Alzheimer’s disease brain contains tau fractions with differential prion-like activities
Open Access
- 17 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Acta Neuropathologica Communications
- Vol. 9 (1), 1-18
- https://doi.org/10.1186/s40478-021-01127-4
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.Keywords
Funding Information
- Alzheimer's Association (DSAD-15-363172)
- Graduate Research and Innovation Projects of Jiangsu Province (KYCX18_2413)
This publication has 62 references indexed in Scilit:
- Brain homogenates from human tauopathies induce tau inclusions in mouse brainProceedings of the National Academy of Sciences of the United States of America, 2013
- Synthetic Tau Fibrils Mediate Transmission of Neurofibrillary Tangles in a Transgenic Mouse Model of Alzheimer's-Like TauopathyJournal of Neuroscience, 2013
- Trans-cellular Propagation of Tau Aggregation by Fibrillar SpeciesOnline Journal of Public Health Informatics, 2012
- Propagation of Tau Pathology in a Model of Early Alzheimer's DiseaseNeuron, 2012
- Trans-Synaptic Spread of Tau Pathology In VivoPLOS ONE, 2012
- Seeding of Normal Tau by Pathological Tau Conformers Drives Pathogenesis of Alzheimer-like TanglesOnline Journal of Public Health Informatics, 2011
- Transmission and spreading of tauopathy in transgenic mouse brainNature, 2009
- Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer's diseaseBrain, 2009
- Propagation of Tau Misfolding from the Outside to the Inside of a CellOnline Journal of Public Health Informatics, 2009
- Neuropathological stageing of Alzheimer-related changesActa Neuropathologica, 1991