Seeding of Normal Tau by Pathological Tau Conformers Drives Pathogenesis of Alzheimer-like Tangles*

By Jing L Guo, V. Lee. Journal of Biological Chemistry, 2011

632 citations recorded by the source corpus.

Neurofibrillary tangles (NFTs) in Alzheimer disease and related tauopathies are composed of insoluble hyperphosphorylated Tau protein, but the mechanisms underlying the conversion of highly soluble Tau into insoluble NFTs remain elusive. Here, we demonstrate that introduction of minute quantities of misfolded preformed Tau fibrils (Tau pffs) into Tau-expressing cells rapidly recruit large amounts of soluble Tau into filamentous inclusions resembling NFTs with unprecedented efficiency, suggesting a “seeding”-recruitment process as a highly plausible mechanism underlying NFT formation in vivo. Consistent with the emerging concept of prion-like transmissibility of disease-causing amyloidogenic proteins, we found that spontaneous uptake of Tau pffs into cells is likely mediated by endocytosis, suggesting a potential mechanism for the propagation of Tau lesions in tauopathy brains. Furthermore, sequestration of soluble Tau by pff-induced Tau aggregates attenuates microtubule overstabilization in Tau-expressing cells, supporting the hypothesis of a Tau loss-of-function toxicity in cells harboring NFTs. In summary, our study establishes a cellular system that robustly develops authentic NFT-like Tau aggregates, which provides mechanistic insights into NFT pathogenesis and a potential tool for identifying Tau-based therapeutics.

Subfields: Molecular Biology, Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/66bac2e8b1507ad52a916cf1b977686eeae7f519

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Citations in the corpus

Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012, neutral): “The current clinical trial literature is compatible with the idea that A A P-related substances kindle a self-propagating process related to neocortical NFTs, as has been hypothesized (266 Y 269).”
Pathogenic Protein Seeding in Alzheimer’s Disease and Other Neurodegenerative Disorders (2011, background): “In vitro, aggregates of tau, a-synuclein, polyglutamine, and SOD1 all can be taken up by endocytosis and induce the misfolding of the corresponding intracellular proteins; moreover, cytoplasmic protein aggregates can translocate from one cultured cell to another.(64,66,80,81,83,84,86,88) The mode of”
Primary age-related tauopathy (PART): a common pathology associated with human aging (2014, background): “Theoretically, given experimental findings that tau pathology might be propagated trans-synaptically [34, 35, 38, 46, 47, 57, 91], it is notable that PART-type pathology generally does not progress to the isocortical Braak stages (i.e., V–VI), remaining relatively restricted neuroanatomically even…”
The Glymphatic System – A Beginner's Guide (2015, neutral): “initiation of fibrillary aggregates, which attracts additional tau leading to formation of neurofibrillary tangles ultimately resulting in a prion-like spread of the pathology [101, 102].”