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Cited by 395Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsAutophagy in Disease and Therapy

RIPK1 mediates a disease-associated microglial response in Alzheimer’s disease

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Ofengeim, Dimitry, Mazzitelli, Sonia, Ito, Yasushi, DeWitt, Judy Park, Mifflin, Lauren, Zou, Chengyu, Das, Sudeshna, Adiconis, Xian +5 more·2017·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1714175114PMC PMC5642727
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Abstract

Significance: Dysfunction of microglia plays a fundamental role in the pathogenesis of Alzheimer’s disease (AD), the most common form of dementia. However, there is a lack of knowledge about targets that can be safely manipulated for modulating microglia for the treatment of AD. The presence of a unique subtype of disease-associated microglia (DAM) has recently been implicated in mediating pathogenesis of AD. However, the mechanism that promotes the development of DAM is unclear, nor is it known how DAM may modulate the progression of AD. This study demonstrates that RIPK1-dependent transcription promotes DAM and lysosomal defects to mediate the accumulation of amyloid plaques in AD. Thus, targeting RIPK1 may provide an important therapeutic strategy for the treatment of AD.

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  • Altered Cst7 expression is associated with microglial dysfunction leading to impairment of Aβ clearance.

    “Previous studies associated altered Cst7 expression with microglial dysfunction leading to impairment of Aβ clearance,37”

    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 [37]

    The Discussion (page unavailable) says increased Cst7 expression caused microglial dysfunction by blocking lysosomal trafficking, and the Results show that Cst7 expression attenuated lysosomal function in a microglial cell line. The paper proposes that reducing Cst7 might promote Aβ clearance; it does not establish that altered Cst7 expression impaired Aβ clearance. (LLM, conf=0.85)

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Authors
Ofengeim, D., Mazzitelli, S., Ito, Y., DeWitt, J. P., Mifflin, L., Zou, C., Das, S., Adiconis, X., Chen, H., Zhu, H., Kelliher, M. A., Levin, J. Z., & Yuan, J.
Affiliations
  • Harvard University (US)
  • Broad Institute (US)
  • University of Massachusetts Chan Medical School (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2017-09-13
Volume
114
Issue
41
Pages
E8788-E8797
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1714175114
PMC
PMC5642727
OpenAlex
W2754483429
Cited by
395
References
16
Citations by year
2026: 37 · 2025: 40 · 2024: 56 · 2023: 49 · 2022: 52 · 2021: 54 · 2020: 38 · 2019: 37 · 2018: 26 · 2017: 5
FWCI
14.44
Type
journal article
Language
en
Open access
Licence
www.pnas.org/site/misc/userlicense.xhtml (vor, 209 d)
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
Funders
  • HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) (1R01NS082257)
  • HHS | National Institutes of Health (NIH) (1R01AG047231)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
RIPK1, disease-associated microglia, Alzheimer's disease, cystatin F, lysosomal pathway, microglial activation, phagocytosis, neuroinflammation, therapeutic target
MeSH terms
Alzheimer Disease, Animals, Cells, Cultured, Disease Models, Animal, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Phenotype, Biomarkers, Cytokines, Microglia, Gene Expression Profiling, Mice, Receptor-Interacting Protein Serine-Threonine Kinases, Presenilin-1

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