Home › Research › Lewy body dementia
Propagation of tau misfolding from the outside to the inside of a cell
Frost B, Jacks RL, Diamond MI.. The Journal of biological chemistry, 2009-03-11
Topic: Brain proteins, microglia and lab models
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.
Key findings
- 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.
Why it matters
In Alzheimer's and related diseases, tau pathology starts in small brain regions and later spreads, and this study tested whether clumped tau can carry its misfolded shape into cells "similar to prions." In cultured cells, tau clumps (aggregates), but not single tau molecules, were taken up and made the cell's own tau form fibrils; those new fibrils could seed more fibrils in a test tube and passed between neighbouring cells. This is laboratory cell work that suggests one way tau misfolding might spread; it did not study people or animals and does not test a treatment.
Study details
- Evidence strengthLow
How this study scored 54/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (The Journal of biological chemistry) |
| Journal's citation record | 4 / 4 | Journal of Biological Chemistry: journal h-index 780 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2009 — within 20 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 7 / 7 | Cited 1,262 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 66.4 citations a year over 19 year(s) since 2009 |
| Impact for its field and year | 5 / 6 | Cited 38.7× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 4 / 6 | Cited by 46 other studies in this library |
| Still being cited | 3 / 4 | Cited 185 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Marc I. Diamond: h-index 61 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of California, San Francisco: institution h-index 1,915 (OpenAlex) |
| Multi-centre collaboration | 0 / 3 | OpenAlex lists 1 institution(s) in 1 country — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 19282288) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 54 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1074/jbc.m808759200
- PubMed: 19282288
- Original source →
- Free full text: Journal of Biological Chemistry →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. Check the citation against the original before you use it.
APA 7th
Frost, B., Jacks, R. L., & Diamond, M. I. (2009). Propagation of tau misfolding from the outside to the inside of a cell. The Journal of biological chemistry. https://doi.org/10.1074/jbc.m808759200
Vancouver
Frost B, Jacks RL, Diamond MI. Propagation of tau misfolding from the outside to the inside of a cell. The Journal of biological chemistry. 2009. doi:10.1074/jbc.m808759200. PMID: 19282288.
BibTeX
@article{frost2009-19282288,
author = {Frost, B. and Jacks, R. L. and Diamond, M. I.},
title = {{Propagation of tau misfolding from the outside to the inside of a cell}},
journal = {The Journal of biological chemistry},
year = {2009},
doi = {10.1074/jbc.m808759200},
pmid = {19282288},
url = {https://doi.org/10.1074/jbc.m808759200}
}
Studies this one cites
Referenced by this study and also in the alzhub library, so you can read them here.
Later studies that cite this one
46 studies in the alzhub library list this one in their references. Showing the 8 highest-scoring.
Related studies in Lewy body dementia
Also tagged “phosphorylated”
732 studies in the library carry the topic tag “phosphorylated”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 732 tagged studies.