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

Integrative approach to sporadic Alzheimer’s disease: deficiency of TYROBP in a tauopathy mouse model reduces C1q and normalizes clinical phenotype while increasing spread and state of phosphorylation of tau

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Audrain, Mickael, Haure-Mirande, Jean-Vianney, Wang, Minghui, Kim, Soong Ho, Fanutza, Tomas, Chakrabarty, Paramita, Fraser, Paul, St George-Hyslop, Peter H. +6 more·2019·Molecular Psychiatry
DOI 10.1038/s41380-018-0258-3PMC PMC6447470
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Abstract

TYROBP/DAP12 forms complexes with ectodomains of immune receptors (TREM2, SIRPβ1, CR3) associated with Alzheimer’s disease (AD) and is a network hub and driver in the complement subnetwork identified by multi-scale gene network studies of postmortem human AD brain. Using transgenic or viral approaches, we characterized in mice the effects of TYROBP deficiency on the phenotypic and pathological evolution of tauopathy. Biomarkers usually associated with worsening clinical phenotype (i.e., hyperphosphorylation and increased tauopathy spreading) were unexpectedly increased in MAPT P301S ; Tyrobp -/- mice despite the improved learning behavior and synaptic function relative to controls with normal levels of TYROBP. Notably, levels of complement cascade initiator C1q were reduced in MAPT P301S ; Tyrobp -/- mice, consistent with the prediction that C1q reduction exerts a neuroprotective effect. These observations suggest a model wherein TYROBP-KO-(knock-out)-associated reduction in C1q is associated with normalized learning behavior and electrophysiological properties in tauopathy model mice despite a paradoxical evolution of biomarker signatures usually associated with neurological decline.

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  • Manipulation of molecules involved in immune/microglial function in either direction may result in detrimental or exacerbated pathological outcomes.

    “However, as we have previously seen in our studies modulating Tyrobp expression, manipulation of molecules involved in immune/microglial function in either direction may result in detrimental or exacerbated pathological outcomes.49,53,54,56”

    From Microglial <i>INPP5D</i> limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [56]

    The Discussion reports that Tyrobp deletion increased tau phosphorylation and spread in mouse models, supporting the possibility of adverse pathological effects from reducing a microglial molecule. It also reports improved clinical and functional features. This paper does not establish that manipulation in the opposite direction produces detrimental outcomes. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Manipulation of Trem2, Tyrobp, Cx3cl1/Cx3cr1, IL1β, and IFN-γ have opposing effects on amyloid and tau pathologies.

    “Indeed, manipulation of expression of Trem2, Tyrobp, Cx3cl1/Cx3cr1, IL1β, and IFN-γ have all been shown to have opposing effects on amyloid and tau pathologies [49–51, 55–65].”

    From Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways (2022) · cites this paper as [55]

    The Discussion (page unavailable) reports that TYROBP deficiency increases tau phosphorylation and spread, while the Introduction (page unavailable) describes reduced microglial clustering around amyloid plaques in earlier TYROBP studies. These passages support effects on both processes, but do not establish opposing effects on amyloid and tau pathologies. This source also does not substantiate the listed Cx3cl1/Cx3cr1, IL1β, or IFN-γ manipulations; the sentence cites other papers as well. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • The dichotomy of immune effects on amyloid and tau has been demonstrated in multiple models of Trem2 and Tyrobp.

    “More recently, this dichotomy has been elegantly demonstrated in multiple models of Trem2 and Tyrobp [49–51, 55–59].”

    From Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways (2022) · cites this paper as [55]

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Authors
Audrain, M., Haure-Mirande, J.-V., Wang, M., Kim, S. H., Fanutza, T., Chakrabarty, P., Fraser, P., St George-Hyslop, P. H., Golde, T. E., Blitzer, R. D., Schadt, E. E., Zhang, B., Ehrlich, M. E., & Gandy, S.
Affiliations
  • Icahn School of Medicine at Mount Sinai (US)
  • University of Florida (US)
  • University of Toronto (CA)
Corresponding author
  • Ehrlich, Michelle E.
  • Gandy, Sam
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2018-10-03
Volume
24
Issue
9
Pages
1383-1397
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/s41380-018-0258-3
PMC
PMC6447470
OpenAlex
W2894623022
Cited by
68
References
55
Citations by year
2026: 2 · 2025: 8 · 2024: 10 · 2023: 7 · 2022: 13 · 2021: 11 · 2020: 7 · 2019: 8 · 2018: 1 · 2017: 1
FWCI
4.64
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • BrightFocus Foundation (A2018253F, A2016482F)
  • Cure Alzheimer's Fund (U01AG046170)
  • Wellcome Trust (203249/Z/16/Z)
  • National Institute on Aging (AG 005138, R56AG058469, R01AG057907, RF1AG058469, U01AG046170, P50AG005138, R01AG055798, RF1AG059319, R01AG061894, P30AG066514)
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
Alzheimer's disease, sporadic Alzheimer's disease, TYROBP, DAP12, tauopathy, C1q, complement system, tau phosphorylation, TREM2, CR3, neuroprotection, learning behavior, synaptic function, mouse model
MeSH terms
Alzheimer Disease, Animals, Brain, Disease Models, Animal, Humans, Membrane Proteins, Mice, Transgenic, Phenotype, Phosphorylation, Complement C1q, Amyloid beta-Protein Precursor, tau Proteins, Microglia, Mice, Knockout, Tauopathies, Animals, Genetically Modified, Adaptor Proteins, Signal Transducing, Mice, Plaque, Amyloid

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