Microglial and neuronal fates following inhibition of CSF-1R in synucleinopathy mouse model

Michiyo Iba; Yeon-Joo Lee; Liam Horan-Portelance; Katherine Chang; Marcell Szabo; Robert A Rissman; Sungyong You; Eliezer Masliah; Changyoun Kim

doi:10.1016/j.bbi.2024.09.016

Microglial and neuronal fates following inhibition of CSF-1R in synucleinopathy mouse model

Brain Behav Immun. 2024 Sep 14:123:254-269. doi: 10.1016/j.bbi.2024.09.016. Online ahead of print.

Authors

Michiyo Iba¹, Yeon-Joo Lee², Liam Horan-Portelance¹, Katherine Chang¹, Marcell Szabo¹, Robert A Rissman³, Sungyong You⁴, Eliezer Masliah⁵, Changyoun Kim⁶

Affiliations

¹ Molecular Neuropathology Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
² Departments of Urology and Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
³ Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
⁴ Departments of Urology and Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Electronic address: [email protected].
⁵ Molecular Neuropathology Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA; Division of Neuroscience, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: [email protected].
⁶ Molecular Neuropathology Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: [email protected].

PMID: 39284516
DOI: 10.1016/j.bbi.2024.09.016

Abstract

Synucleinopathies are age-related neurological disorders characterized by the abnormal accumulation of α-synuclein (α-syn) in neuronal and non-neuronal cells. It has been proposed that microglial cells play an important role in synucleinopathy neuroinflammation, as well as homeostatically, such as in the clearance of α-syn aggregates in the brain. Here, we examined the effects of microglia on the pathogenesis of synucleinopathies by cell depletion in a mouse model of synucleinopathies. For this purpose, we treated non-transgenic (Non-tg) and α-synuclein transgenic (α-syn-tg) mice with pexidartinib (PLX3397), a tyrosine kinase inhibitor of colony-stimulating factor 1 receptor (CSF-1R). Neuropathological and immunoblot analysis confirmed that Iba-1 immunoreactive microglial cells were decreased by 95% following PLX3397 treatment in Non-tg and α-syn-tg mice. The level of total α-syn in the Triton X-insoluble fraction of brain homogenate was significantly decreased by microglial depletion in the α-syn-tg mice, while the level of Triton X-soluble human α-syn was not affected. Furthermore, the number of p-α-syn immunoreactive inclusions was reduced in α-syn-tg mice treated with PLX3397. Microglial depletion also ameliorated neuronal and synaptic degeneration in α-syn-tg mice, thereby resulted partially improving the motor behavioral deficit in α-syn-tg mice. Moreover, we demonstrated that microglia that survived post-PLX3397 treatment (PLX-resistant microglia) have lower expressions of CSF-1R, and microglial transcriptome analysis further elucidated that PLX-resistant microglia have unique morphology and transcriptomic signatures relative to vehicle-treated microglia of both genotypes; these include differences in definitive microglial functions such as their immune response, cell mobility, cell-cell communications, and regulation of neural homeostasis. Therefore, we suggest that microglia play a critical role in the pathogenesis of synucleinopathies, and that modulation of microglial status might be an effective therapeutic strategy for synucleinopathies.

Published by Elsevier Inc.