# Complement receptor 3 (CR3)-dependent microglial synapse elimination drives Parkinson’s disease pathogenesis in systemic inflammation

## TL;DR

Systemic inflammation triggers early synaptic loss in Parkinson’s disease through microglial activity, which can be halted by targeting complement receptor 3.

## Contribution

Identifies complement receptor 3 as a key driver of microglial synapse elimination in Parkinson’s disease progression.

## Key findings

- Synaptic loss in the midbrain occurs one day after LPS administration, preceding DA neuron degeneration.
- Microglial activation and synaptic engulfment are early features of PD pathogenesis.
- CR3 inhibition rescues synaptic integrity and prevents neurodegeneration in the model.

## Abstract

Although systemic inflammation has been implicated in PD pathogenesis, the underlying mechanisms remain poorly understood. In this study, we investigate the pathological events in a systemic inflammation-induced PD mouse model. We demonstrate that synaptic loss in the midbrain occurs as early as 1 day after the final lipopolysaccharide (LPS) administration, preceding dopaminergic (DA) neuron degeneration, which was observed only at later stages (14 days). Early microglial activation in the midbrain is detected, accompanied by excessive synaptic engulfment, suggesting a critical role of microglia-dependent synapse elimination in PD pathogenesis. Furthermore, we identify the complement receptor 3 (CR3) as a key mediator of microglial synaptic engulfment, revealing that its inhibition rescues synaptic integrity and prevents neurodegeneration. Our results contribute to a deeper understanding of early events of PD progression driven by systemic inflammation and provide early intervention strategies targeting microglial complement signaling to halt PD progression.