SYSTEMATIC REVIEW article
Front. Aging Neurosci.
Sec. Neuroinflammation and Neuropathy
The impact of CSF1R inhibitor-mediated microglial depletion in rodent models of Alzheimer's and Parkinson's disease: a systematic review and meta-analysis
Provisionally accepted
- University of São Paulo, São Paulo, Brazil
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Microglia are central nervous system immune cells that support brain homeostasis but can adopt harmful roles in neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD), depending on the disease stage and progression. Thus, targeting microglia through depletion has emerged as a potential therapeutic approach. This systematic review and meta-analysis aim to evaluate the effects of microglial depletion using colony-stimulating factor 1 receptor (CSF1R) inhibitors, such as PLX3397 and PLX5622, in preclinical models of AD and PD. Twenty-six AD and seventeen PD preclinical studies were selected. In PD models, most studies reported neuroprotective effects after microglial depletion, though a few showed detrimental outcomes, particularly with shorter depletion protocols. Notably, almost all studies induced microglial depletion prior to or during disease onset, underscoring a major research gap. Behavioral results were contradictory, as some reported beneficial effects while others showed no effect or worsened behavior. In AD models, results were more variable, but many studies observed reduced neuroinflammation, improved cognition, and decreased amyloid-beta and tau pathology. Meta-analyses showed no overall reduction in dopaminergic neuron loss in PD or amyloid-beta levels in AD, though longer depletion protocols showed more favorable trends in both diseases. Despite the few reports, repopulation following microglial depletion may constitute a promising approach. Microglial depletion, via PLX3397 and PLX5622, may offer therapeutic potential for both AD and PD, although high heterogeneity and variability among studies are a clear limitation. Further studies are needed, particularly those assessing post-onset intervention, sex-specific effects, and broader behavioral and pathological endpoints to better understand the therapeutic potential of microglial modulation.
Keywords: CSF1-R inhibition, Microglial depletion, Microglial repopulation, neurodegeneration, Neuroprotection
Received: 28 Oct 2025; Accepted: 02 Feb 2026.
Copyright: © 2026 Ferreira, Santos-Silva, Muratori and Britto. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Ana Flavia Fernandes Ferreira
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