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Cited by 78Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsDementia and Cognitive Impairment Research

Acute Trem2 reduction triggers increased microglial phagocytosis, slowing amyloid deposition in mice

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Schoch, Kathleen M., Ezerskiy, Lubov A., Morhaus, Michaela M., Bannon, Riley N., Sauerbeck, Andrew D., Shabsovich, Mark, Jafar-nejad, Paymaan, Rigo, Frank +1 more·2021·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2100356118PMC PMC8271763
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Abstract

Significance: Alzheimer’s disease (AD) remains a significant health burden within the aging population and currently lacks therapies that effectively target pathological events to halt the development or progression of AD. The gene TREM2 appears to influence abnormal protein accumulations in AD through the brain’s immune cells; however, it is not clear if and when TREM2 might be targeted in disease to limit pathology or the immune response. We used antisense oligonucleotides (ASOs) to reduce Trem2 levels in the mouse brain at specific times in disease and investigated amyloid protein accumulations, microglial responses, and genetic signatures. ASO-mediated Trem2 lowering during late-stage disease reduced amyloid pathology, which may have been triggered by an acute activation of microglia to engulf and clear amyloid deposits.

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  • The timing of gene and/or total microglial manipulation is critical.

    “Notably, the timing of gene and/or total microglial manipulation is also critical,47”

    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 [47]

    The Abstract reports that Trem2 reduction reduced amyloid deposition when administered during late-stage pathology but not before or at an early stage, supporting the importance of timing for this gene intervention. The paper does not establish that the timing of total microglial manipulation is critical. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Time- and/or dose-dependent intervening of TREM2 signaling may be therapeutic for AD.

    “indicating a time- and/or dose-dependent intervening the TREM2 signaling for the therapy of AD.540”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [540]

  • Antisense oligonucleotides that transiently reduce TREM2 expression at late stages of plaque pathology significantly reduced plaque deposition and microglia association around plaque deposits.

    “Lastly, using antisense oligonucleotides that potently but transiently reduce TREM2 expression at late stages of plaque pathology significantly reduced plaque deposition and microglia association around plaque deposits, indicating a time- and/or dose-dependent intervening the TREM2 signaling for the therapy of AD.540”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [540]

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Authors
Schoch, K. M., Ezerskiy, L. A., Morhaus, M. M., Bannon, R. N., Sauerbeck, A. D., Shabsovich, M., Jafar-nejad, P., Rigo, F., & Miller, T. M.
Affiliations
  • Washington University in St. Louis (US)
  • Ionis Pharmaceuticals, Carlsbad, CA 92010
  • Ionis Pharmaceuticals (United States) (US)
Corresponding author
  • Schoch, Kathleen M.
  • Miller, Timothy M.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2021-06-29
Volume
118
Issue
27
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.2100356118
PMC
PMC8271763
OpenAlex
W3176037250
Cited by
78
References
16
Citations by year
2026: 10 · 2025: 16 · 2024: 15 · 2023: 18 · 2022: 12 · 2021: 7
FWCI
5.21
Type
journal article
Language
en
Open access
Licence
www.pnas.org/site/aboutpnas/licenses.xhtml (vor, 183 d)
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • BrightFocus Foundation (A2018169S)
  • HHS | NIH | National Institute of Neurological Disorders and Stroke (R01NS078398)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
TREM2, Alzheimer's disease, amyloid deposition, microglial phagocytosis, antisense oligonucleotides, gene silencing, microglial activation, amyloid clearance, late-stage disease, brain immune response
MeSH terms
Amyloid, Animals, Brain, Membrane Glycoproteins, Mice, Transgenic, Phagocytosis, Phosphorylation, Receptors, Immunologic, Biomarkers, Up-Regulation, Oligonucleotides, Antisense, Amyloid beta-Protein Precursor, tau Proteins, Microglia, Presenilin-1, Plaque, Amyloid

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