Neuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer’s disease brain
Open accessAbstract
Tau pathology is known to spread in a hierarchical pattern in Alzheimer’s disease (AD) brain during disease progression, likely by trans-synaptic tau transfer between neurons. However, the tau species involved in inter-neuron propagation remains unclear. To identify tau species responsible for propagation, we examined uptake and propagation properties of different tau species derived from postmortem cortical extracts and brain interstitial fluid of tau-transgenic mice, as well as human AD cortices. Here we show that PBS-soluble phosphorylated high-molecular-weight (HMW) tau, though very low in abundance, is taken up, axonally transported, and passed on to synaptically connected neurons. Our findings suggest that a rare species of soluble phosphorylated HMW tau is the endogenous form of tau involved in propagation and could be a target for therapeutic intervention and biomarker development.
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Increasing evidence suggests the transmission of tau pathology is mediated by the release, uptake, and trafficking of pathogenic or misfolded tau aggregates within synaptically connected neurons.
“Increasing evidence suggests the transmission of tau pathology is mediated by the release, uptake, and trafficking of pathogenic or misfolded tau aggregates within synaptically connected neurons9,10.”
From Tau Internalization is Regulated by 6-O Sulfation on Heparan Sulfate Proteoglycans (HSPGs) (2018) · cites this paper as [10]
Abnormally hyperphosphorylated or oligomeric tau can be secreted from neurons into the extracellular space, taken up by other normal neurons, and cause interneuronal transfer of tau pathology and spreading of tau toxicity across different brain regions.
“there is a large amount of evidence indicating that the abnormally hyperphosphorylated or oligomeric tau can be secreted from neurons into the extracellular space, then be taken up by other normal neurons, and finally causes interneuronal transfer of tau pathology and spreading of tau toxicity across different brain regions [59–61]”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [60]
Brain lysates seed Tau aggregation when high-molecular-weight oligomeric hyperphosphorylated (AT8 and AT100) Tau species are present.
“brain lysates seed Tau aggregation when high-molecular-weight oligomeric hyperphosphorylated (AT8 and AT100) Tau species are present (Takeda et al., 2015; Jackson et al., 2016)”
From Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease (2020) · cites this paper as Takeda et al., 2015
The unmodified intrinsically disordered domain from the N terminus to the end of the PRR is overrepresented in LMW Tau, which is seeding incompetent in the biosensor assay.
“we see that the unmodified intrinsically disordered domain encompassing the N terminus to the end of the PRR is overrepresented in LMW Tau, which is seeding incompetent in the biosensor assay (Takeda et al., 2015)”
From Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease (2020) · cites this paper as Takeda et al., 2015
LMW and sarkosyl-soluble Tau fractions do not show positive seeding activity in biosensor assays.
“These Tau fractions do not have positive seeding activity in biosensor assays (Holmes et al., 2014; Takeda et al., 2015).”
From Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease (2020) · cites this paper as Takeda et al., 2015
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 [64]
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References 43 · Cited by 371
- Authors
- Takeda, S., Wegmann, S., Cho, H., DeVos, S. L., Commins, C., Roe, A. D., Nicholls, S. B., Carlson, G. A., Pitstick, R., Nobuhara, C. K., Costantino, I., Frosch, M. P., Müller, D. J., Irimia, D., & Hyman, B. T.
- Affiliations
- Harvard University (US)
- University of North Carolina at Charlotte (US)
- McLaughlin Research Institute (US)
- ETH Zurich (CH)
- Corresponding author
- Hyman, Bradley T.
- ORCID
- Venue
- Nature Communications
- Published
- 2015-10-13
- Volume
- 6
- Issue
- 1
- Pages
- 8490-8490
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4608380
- OpenAlex
- W2215407066
- Cited by
- 371
- References
- 43
- Citations by year
- 2026: 18 · 2025: 32 · 2024: 30 · 2023: 40 · 2022: 35 · 2021: 53 · 2020: 47 · 2019: 30 · 2018: 44 · 2017: 25 · 2016: 15 · 2015: 2
- FWCI
- 21.13
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by)
- ETH Zürich Research Collection (cc-by)
- Funders
- JPB Foundation
- Massachusetts Life Sciences Center
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- Japan Society for the Promotion of Science
- National Institute on Aging (R01AG026249, AG026249, P50 AG05134, P50AG005134)
- National Institute of General Medical Sciences (GM-092804, R01GM092804)
- National Institute of Neurological Disorders and Stroke (P30NS045776)
- National Institute of Biomedical Imaging and Bioengineering (P41EB002503)
- 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
- tau pathology, Alzheimer's disease, neuronal uptake, axonal transport, tau propagation, brain interstitial fluid, tau transgenic mice, biomarkers, therapeutic target
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Animals, Brain, Cell Survival, Female, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Phosphorylation, tau Proteins, Microfluidic Analytical Techniques, HEK293 Cells
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