Propagation of Tau misfolding from the outside to the inside of a cell

Susan E Frost, Rachel L. Jacks, Marc I. Diamond

Research output: Contribution to journalArticle

623 Citations (Scopus)

Abstract

Tauopathies are neurodegenerative diseases characterized by aggregation of the microtubule-associated protein Tau in neurons and glia. Although Tau is normally considered an intracellular protein, Tau aggregates are observed in the extracellular space, and Tau peptide is readily detected in the cerebrospinal fluid of patients. Tau aggregation occurs in many diseases, including Alzheimer disease and frontotemporal dementia. Tau pathology begins in discrete, disease-specific regions but eventually involves much larger areas of the brain. It is unknown how this propagation of Tau misfolding occurs. We hypothesize that extracellular Tau aggregates can transmit a misfolded state from the outside to the inside of a cell, similar to prions. Here we show that extracellular Tau aggregates, but not monomer, are taken up by cultured cells. Internalized Tau aggregates displace tubulin, co-localize with dextran, a marker of fluid-phase endocytosis, and induce fibrillization of intracellular full-length Tau. These intracellular fibrils are competent to seed fibril formation of recombinant Tau monomer in vitro. Finally, we observed that newly aggregated intracellular Tau transfers between co-cultured cells. Our data indicate that Tau aggregates can propagate a fibrillar, misfolded state from the outside to the inside of a cell. This may have important implications for understanding how protein misfolding spreads through the brains of tauopathy patients, and it is potentially relevant to myriad neurodegenerative diseases associated with protein misfolding.

Original languageEnglish (US)
Pages (from-to)12845-12852
Number of pages8
JournalJournal of Biological Chemistry
Volume284
Issue number19
DOIs
StatePublished - May 8 2009
Externally publishedYes

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Tauopathies
Neurodegenerative Diseases
Cultured Cells
Alzheimer Disease
Frontotemporal Dementia
Microtubule-Associated Proteins
Prions
Neurodegenerative diseases
Brain
Extracellular Space
Tubulin
Endocytosis
Dextrans
Neuroglia
Cerebrospinal Fluid
Seeds
Proteins
Pathology
Neurons
Agglomeration

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Propagation of Tau misfolding from the outside to the inside of a cell. / Frost, Susan E; Jacks, Rachel L.; Diamond, Marc I.

In: Journal of Biological Chemistry, Vol. 284, No. 19, 08.05.2009, p. 12845-12852.

Research output: Contribution to journalArticle

Frost, Susan E ; Jacks, Rachel L. ; Diamond, Marc I. / Propagation of Tau misfolding from the outside to the inside of a cell. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 19. pp. 12845-12852.
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