miR155, TREM2, INPP5D: Disease stage and cell type are essential considerations when targeting clinical interventions based on mouse models of Alzheimer’s amyloidopathy
Open accessAbstract
Studies of microglial gene manipulation in mouse models of Alzheimer’s disease (AD) amyloidopathy can cause unpredictable effects on various key endpoints, including amyloidosis, inflammation, neuritic dystrophy, neurodegeneration, and learning behavior. In this Correspondence, we discuss three examples, microRNA 155 (miR155), TREM2, and INPP5D, in which observed results have been difficult to reconcile with predicted results based on precedent, because these six key endpoints do not reliably track together. The pathogenesis of AD involves multiple cell types and complex events that may change with disease stage. We propose that cell-type targeting and timing of intervention are responsible for the sometimes impossibility of predicting whether any prospective therapeutic intervention should aim at increasing or decreasing the level or activity of a particular molecular target.
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The contradictory impacts of Inpp5d loss on plaque load may be attributed to the time point in disease progression at which Inpp5d expression is reduced as well as differences in the AD mouse models.
“The contradictory impacts of Inpp5d loss on plaque load in these studies may be attributed to the time point in disease progression at which Inpp5d expression is reduced as well as the differences in the AD mouse models, as also discussed recently in Gandy and Ehrlich (2023) [174].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [174]
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“Genetic deletion of Trem2 exerted different outcomes depending on the transgenic line, timing of the intervention and the age of the mouse [15].”
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“Finally, the level of TREM2 downregulation also led to unexpected results, in that genetic haploinsufficiency vs total deletion led to opposite effects on tauopathy rather than causing similar effects in a dose-dependent fashion [19].”
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“PS2APP X TREM2 −/− constitutive knockout (12, 19–22 months, both sexes) [16] Decreased Decreased Increased N/A”
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“INPP5D is another microglial AD risk gene identified by GWAS, and four recent Inpp5d knockdown studies in cerebral amyloidosis models were each slightly different in design, and each showed different effects [20–23].”
BackgroundSelf-citation<i>INPP5D</i> deficiency attenuates amyloid pathology in a mouse model of Alzheimer's disease
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“INPP5D is another microglial AD risk gene identified by GWAS, and four recent Inpp5d knockdown studies in cerebral amyloidosis models were each slightly different in design, and each showed different effects [20–23].”
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“However, three recent papers raise the possibility that therapeutic modulation of miR155 might not be straightforward [3, 5, 6].”
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INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia
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- Authors
- Gandy, S., & Ehrlich, M. E.
- Affiliations
- James J. Peters VA Medical Center (US)
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Gandy, Sam
- Ehrlich, Michelle E.
- Venue
- Journal of Neuroinflammation
- Published
- 2023-09-25
- Volume
- 20
- Issue
- 1
- Pages
- 214-214
- ISSN
- 1742-2094 (ISSN-L)
- PMC
- PMC10518910
- OpenAlex
- W4387018681
- Cited by
- 11
- References
- 8
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 3 · 2023: 2
- FWCI
- 1.13
- Type
- journal article
- Language
- en
- Update notices
- correction (2023-11-30)
- Open access
- gold
- doi.org
- Locations
- Journal of Neuroinflammation (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute on Aging (U01AG046170)
- Cure Alzheimer's Fund
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- Alzheimer's disease, amyloid pathology, miR-155, TREM2, INPP5D, microglia, mouse model, disease stage, intervention timing, amyloidosis, neuroinflammation, neurodegeneration, therapeutic target
- MeSH terms
- Alzheimer Disease, Amyloidosis, Animals, Cell Movement, Disease Models, Animal, MicroRNAs, Mice
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