The impact of CSF1R inhibitor-mediated microglial depletion in rodent models of Alzheimer's and Parkinson's disease: a systematic review and meta-analysis.
Level 5 - mechanism / opinion, no new human data
Systematic review of preclinical animal studies with no human clinical data (Level 1 by non-clinical design analogy).
PubMed 41822299 · doi:10.3389/fnagi.2026.1733682
What was done
A systematic review and meta-analysis (PROSPERO CRD420251075163) evaluating the effects of microglial depletion via CSF1R inhibitors, including PLX3397 and PLX5622, in preclinical rodent models of Alzheimer's disease and Parkinson's disease across 43 included studies (26 Alzheimer's disease and 17 Parkinson's disease).
What was found
The abstract reports no numerical values, effect sizes, or confidence intervals. Preclinical Parkinson's disease studies mostly reported neuroprotection, though shorter depletion durations sometimes showed detrimental outcomes, and behavioral effects were contradictory (beneficial, neutral, or worsened). In Alzheimer's disease models, individual studies frequently reported lower neuroinflammation, decreased amyloid-beta and tau pathology, and improved cognition. However, quantitative meta-analyses demonstrated no overall reduction in dopaminergic neuron loss in Parkinson's disease models or amyloid-beta burden in Alzheimer's disease models, although longer depletion protocols showed more favorable trends.
Why it matters
This review synthesizes the preclinical evidence for CSF1R-targeted microglial clearance, showing that despite widespread mechanistic interest, meta-analytic outcomes do not demonstrate consistent reductions in hallmark pathologies across rodent models.
Limits
Findings are limited entirely to rodent models with no human validation. The abstract reports no numerical point estimates or variance metrics. High heterogeneity was observed across studies. Almost all included experiments initiated depletion before or at disease onset rather than after symptom manifestation, and sex-specific differences as well as post-depletion repopulation remain understudied.
Cited by
- context Phase 1 clinical trials have tested drugs designed to kill or deplete microglia to prevent Alzheimer's disease.