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Cited by 68Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Bassoon contributes to tau-seed propagation and neurotoxicity

Open access
Martinez, Pablo, Patel, Henika, You, Yanwen, Jury, Nur, Perkins, Abigail, Lee-Gosselin, Audrey, Taylor, Xavier, You, Yingjian +17 more·2022·Nature Neuroscience
DOI 10.1038/s41593-022-01191-6PMC PMC9708566
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Abstract

Tau aggregation is a defining histopathological feature of Alzheimer’s disease and other tauopathies. However, the cellular mechanisms involved in tau propagation remain unclear. Here, we performed an unbiased quantitative proteomic study to identify proteins that specifically interact with this tau seed. We identified Bassoon (BSN), a presynaptic scaffolding protein, as an interactor of the tau seed isolated from a mouse model of tauopathy, and from Alzheimer’s disease and progressive supranuclear palsy postmortem samples. We show that BSN exacerbates tau seeding and toxicity in both mouse and Drosophila models for tauopathy, and that BSN downregulation decreases tau spreading and overall disease pathology, rescuing synaptic and behavioral impairments and reducing brain atrophy. Our findings improve the understanding of how tau seeds can be stabilized by interactors such as BSN. Inhibiting tau-seed interactions is a potential new therapeutic approach for neurodegenerative tauopathies.

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  • HMW tau-containing particles are one of the predominant toxic entities.

    “Our laboratory has recently demonstrated that the primary source of tau seeding activity in AD cases, corresponds to soluble high molecular weight (HMW) tau species; thus, HMW tau-containing particles are one of the predominant toxic entities [60].”

    From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [60]

    The Results section ‘BSN is associated with tau pathology in human tauopathy brain tissue’ (page unavailable) identifies the HMW fraction as having the strongest tau-seeding activity in AD patient brains. It does not establish that HMW tau-containing particles are predominant toxic entities; seeding activity alone does not demonstrate that ranking of toxicity. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • The plaque microenvironment in AsymAD individuals does not facilitate the formation of soluble tau species with strong seeding activity, unlike in neurotoxic tau oligomers formation in AD brains.

    “Therefore, the evidence provided in the current study suggests that the plaque microenvironment in AsymAD individuals does not facilitate the formation of soluble tau species with strong seeding activity, unlike in neurotoxic tau oligomers formation in AD brains [60].”

    From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [60]

    The Results section on human tauopathy brain tissue reports strong seeding activity in high-molecular-weight tau from AD brains, supporting the AD side of the contrast. It describes those seeds as predominantly twisted filaments, not oligomers, and does not examine plaque microenvironments in AsymAD individuals. The AsymAD inference is framed as the citing authors’ own finding rather than a result attributed to this source. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • The gating strategy for singlet selection, CFP background removal, and FRET+ signal (BV510 channel) was performed as previously described.

    “Our gating strategy for singlet selection, CFP background removal, and FRET+ signal (BV510 channel) were performed as previously described (Martinez et al., 2022).”

    From Network analysis identifies strain-dependent response to tau and tau seeding-associated genes (2023) · cites this paper as Martinez et al., 2022

  • Seeding activity has been shown to identify the action of high molecular weight tau and to differentiate between specific conformers in 3R/4R tau diseases.

    “As a pathological readout, seeding activity has been shown to identify the action of high molecular weight tau (Martinez et al., 2022) and even differentiate between specific conformers in 3R/4R tau diseases (Kraus et al., 2019).”

    From Network analysis identifies strain-dependent response to tau and tau seeding-associated genes (2023) · cites this paper as Martinez et al., 2022

  • Previous research has demonstrated that interactors like Bassoon (Bsn) contribute to the ability of tau to seed and induce neurotoxicity.

    “Our previous research has demonstrated that interactors like Bassoon (Bsn) contribute to the ability of tau to seed and induce neurotoxicity (Martinez et al., 2022).”

    From Network analysis identifies strain-dependent response to tau and tau seeding-associated genes (2023) · cites this paper as Martinez et al., 2022

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Authors
Martinez, P., Patel, H., You, Y., Jury, N., Perkins, A., Lee-Gosselin, A., Taylor, X., You, Y., Viana Di Prisco, G., Huang, X., Dutta, S., Wijeratne, A. B., Redding-Ochoa, J., Shahid, S. S., Codocedo, J. F., Min, S., Landreth, G. E., Mosley, A. L., Wu, Y.-C., McKinzie, D. L., Rochet, J.-C., Zhang, J., Atwood, B. K., Troncoso, J., & Lasagna-Reeves, C. A.
Affiliations
  • Indiana University School of Medicine (US)
  • Purdue University West Lafayette (US)
  • Indiana University Indianapolis (US)
  • Johns Hopkins University (US)
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2022-11-07
Volume
25
Issue
12
Pages
1597-1607
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/s41593-022-01191-6
PMC
PMC9708566
OpenAlex
W4308469604
Cited by
68
References
12
Citations by year
2026: 16 · 2025: 20 · 2024: 19 · 2023: 13
FWCI
8.05
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by)
Funders
  • Alzheimer’s Association (AARFD-21-847663, AARGD-591887)
  • U.S. Department of Health & Human Services | National Institutes of Health (U19AG033655)
  • U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (R01NS119280,)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
bassoon, tau seeding, tau propagation, tauopathy, Alzheimer's disease, progressive supranuclear palsy, protein-protein interaction, neurotoxicity, synaptic dysfunction, brain atrophy, therapeutic target
MeSH terms
Alzheimer Disease, Animals, Brain, tau Proteins, Tauopathies, Proteomics, Mice

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