Seed‐competent high‐molecular‐weight tau species accumulates in the cerebrospinal fluid of Alzheimer's disease mouse model and human patients
Open accessAbstract
Objective: Cerebrospinal fluid (CSF) tau is an excellent surrogate marker for assessing neuropathological changes that occur in Alzheimer's disease (AD) patients. However, whether the elevated tau in AD CSF is just a marker of neurodegeneration or, in fact, a part of the disease process is uncertain. Moreover, it is unknown how CSF tau relates to the recently described soluble high‐molecular‐weight (HMW) species that is found in the postmortem AD brain and can be taken up by neurons and seed aggregates. Methods: We have examined seeding and uptake properties of brain extracellular tau from various sources, including interstitial fluid (ISF) and CSF from an AD transgenic mouse model and postmortem ventricular and antemortem lumbar CSF from AD patients. Results: We found that brain ISF and CSF tau from the AD mouse model can be taken up by cells and induce intracellular aggregates. Ventricular CSF from AD patients contained a rare HMW tau species that exerted a higher seeding activity. Notably, the HMW tau species was also detected in lumbar CSF from AD patients, and its levels were significantly elevated compared to control subjects. HMW tau derived from CSF of AD patients was seed competent in vitro. Interpretation: These findings suggest that CSF from an AD brain contains potentially bioactive HMW tau species, giving new insights into the role of CSF tau and biomarker development for AD. Ann Neurol 2016;80:355–367
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Within the AD cohort, some samples contained more bioactive, propagation-prone material per unit tau than others.
“Moreover, within the AD cohort, some samples seemed to contain more bioactive, propagation-prone material (per unit of tau protein) than others.”
From All the Tau We Cannot See (2023) · cites this paper as [67]
Control samples did not contain oligomeric tau species, and early eluting fractions from AD brain contained tau with proteopathic seed-like ability.
“In carrying out these experiments, Hyman and colleagues noticed that control samples did not contain any oligomeric tau species and that the early eluting fractions contained tau that had proteopathic seed-like ability (67).”
From All the Tau We Cannot See (2023) · cites this paper as [67]
Soluble, oligomeric tau can be isolated from human AD brain using homogenization, centrifugation, and size exclusion chromatography.
“Soluble, oligomeric tau can also be isolated from human AD brain using simple homogenization, centrifugation, and size exclusion chromatography steps (67) (Figure 3).”
From All the Tau We Cannot See (2023) · cites this paper as [67]
Previous reports show that on SDD-AGE, low-molecular-weight tau accumulates at the bottom of the gel and high-molecular-weight tau oligomers appear as smears at the top.
“Previous reports of HMW and LMW tau run on SDD-AGE show an accumulation of LMW tau at the bottom of the gel with smears of HMW tau oligomers at the top (7, 63–65).”
From Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy (2017) · cites this paper as [65]
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- Authors
- Takeda, S., Commins, C., DeVos, S. L., Nobuhara, C. K., Wegmann, S., Roe, A. D., Costantino, I., Fan, Z., Nicholls, S. B., Sherman, A. E., Trisini Lipsanopoulos, A. T., Scherzer, C. R., Carlson, G. A., Pitstick, R., Peskind, E. R., Raskind, M. A., Li, G., Montine, T. J., Frosch, M. P., & Hyman, B. T.
- Affiliations
- Harvard University (US)
- Ann Romney Center for Neurological Diseases Brigham and Women's Hospital Boston MA
- Brigham and Women's Hospital (US)
- McLaughlin Research Institute (US)
- University of Washington (US)
- Corresponding author
- Takeda, Shuko
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2016-08-03
- Volume
- 80
- Issue
- 3
- Pages
- 355-367
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC5016222
- OpenAlex
- W2494872295
- Cited by
- 113
- References
- 29
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 11 · 2023: 15 · 2022: 10 · 2021: 13 · 2020: 16 · 2019: 16 · 2018: 9 · 2017: 8 · 2016: 3
- FWCI
- 9.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (PDBP U01 NS082157)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, cerebrospinal fluid tau, tau seeding, interstitial fluid, ventricular CSF, lumbar CSF, transgenic mouse model, tau biomarkers, neurodegeneration
- MeSH terms
- Aged, Alzheimer Disease, Animals, Brain, Female, Humans, Male, Mice, Transgenic, Middle Aged, Biomarkers, tau Proteins, Extracellular Fluid, Mice
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