Depletion of CD169<sup>+</sup> border-associated macrophages induces Parkinson's disease-like behavior.

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Parkinson's disease (PD) and Alzheimer's disease (AD) present with complex behavioral symptoms that can arise in the absence of overt structural brain damage. Recent evidence suggests that border-associated macrophages (BAMs) located at the brain's interfaces regulate central nervous system function, yet the specific roles of distinct BAM subsets remain largely undefined. By reanalyzing single-nucleus RNA sequencing data from postmortem PD brains, we identified a BAM subset expressing CD169 that was significantly reduced in patients compared with controls. To examine their function, we employed CD169-DTR mice to selectively ablate CD169+ BAMs and evaluated behavioral and histological changes. Depletion of CD169+ BAMs induced tremors, abnormal hindlimb reflexes, and heightened anxiety-like behavior without dopaminergic neuron loss. Histological analysis revealed a pronounced reduction of mitral and tufted cells in the olfactory bulb, indicating disruption of olfactory-limbic circuitry. These findings demonstrate that CD169+ BAMs are critical for maintaining neural network stability and motor function, and that their loss can elicit PD-like phenotypes in the absence of classical dopaminergic neurodegeneration. This work establishes a novel mouse model linking brain-border immune cell dysfunction to Parkinsonian pathology and highlights a neuroimmune mechanism that may contribute to the onset of PD-like disorders.

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