# The impact of CSF1R inhibitor-mediated microglial depletion in rodent models of Alzheimer’s and Parkinson’s disease: a systematic review and meta-analysis

## TL;DR

This review and meta-analysis explores the effects of microglial depletion using CSF1R inhibitors in rodent models of Alzheimer’s and Parkinson’s disease, finding mixed but potentially beneficial outcomes.

## Contribution

The study systematically evaluates the impact of microglial depletion in preclinical models of AD and PD, highlighting variability and key research gaps.

## Key findings

- Most PD studies showed neuroprotective effects from microglial depletion, though some reported detrimental outcomes.
- AD models often showed reduced neuroinflammation, improved cognition, and decreased amyloid-beta and tau pathology.
- Meta-analyses found no overall reduction in dopaminergic neuron loss in PD or amyloid-beta levels in AD.

## Abstract

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.

https://www.crd.york.ac.uk/prospero/, identifier CRD420251075163.

Diagram comparing the effects of CSF1R inhibition on Alzheimer’s and Parkinson’s disease brains. Alzheimer’s brain responds with 73 percent improved outcomes like reduced tau pathology and inflammation, while 38 percent show neutral and 11 percent impaired effects. Parkinson’s brain has 64 percent improved outcomes like increased TH counts, with 23 percent neutral and 17 percent impaired effects such as increased degeneration and α-synuclein aggregation. Brain illustrations, effect percentages, and key findings are visually detailed.