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miR155, TREM2, INPP5D: Disease stage and cell type are essential considerations when targeting clinical interventions
Sam Gandy1,2,3, Michelle E Ehrlich4,5,6
1Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. samuel.gandy@mssm.edu.
Abstract:
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.
Insights
Manipulating microglial genes in Alzheimer's disease (AD) mouse models yields unpredictable results. The complex nature of AD pathogenesis means therapeutic targets may need precise cell-type targeting and intervention timing for effective treatment.
Area of Science:
- Neuroscience
- Genetics
- Pathology
Background:
- Alzheimer's disease (AD) research often involves manipulating microglial genes in mouse models.
- Observed effects on amyloidosis, inflammation, neurodegeneration, and behavior can be unpredictable.
Discussion:
- Microglial gene manipulation (e.g., miR155, TREM2, INPP5D) shows inconsistent outcomes.
- Key AD endpoints (amyloidosis, inflammation, neurodegeneration, behavior) do not always correlate predictably.
- AD pathogenesis is multifactorial, involving various cell types and evolving disease stages.
Key Insights:
- Predicting therapeutic intervention outcomes is challenging due to complex AD pathology.
- Observed results from microglial gene manipulation often defy expectations based on prior studies.
- The interconnectedness of AD pathological hallmarks is not always straightforward.
Outlook:
- Future AD therapies require careful consideration of cell-type specificity.
- Timing of therapeutic interventions is critical for managing AD progression.
- Developing effective AD treatments necessitates a nuanced understanding of disease mechanisms.
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