Exosome-mediated microglia-astrocyte interactions drive neuroinflammation in Parkinson's disease with Peli1 as a potential therapeutic target

Min Guo; Ao Guan; Minjie Zhang; Haiqing Li; Weishi Liu; Bangsheng Wu; Weiwei Shen; Tongyao You; Suzhen Liang; Qiang Dong; Jintai Yu; Yanxin Zhao; Mei Cui

doi:10.1016/j.phrs.2025.107908

Pharmacological Research (Sep 2025)

Exosome-mediated microglia-astrocyte interactions drive neuroinflammation in Parkinson's disease with Peli1 as a potential therapeutic target

Min Guo,
Ao Guan,
Minjie Zhang,
Haiqing Li,
Weishi Liu,
Bangsheng Wu,
Weiwei Shen,
Tongyao You,
Suzhen Liang,
Qiang Dong,
Jintai Yu,
Yanxin Zhao,
Mei Cui

Affiliations

Min Guo: Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China
Ao Guan: Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China
Minjie Zhang: Department of Neurology, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
Haiqing Li: Department of Radiology, Huashan Hospital, Fudan University, Shanghai, China
Weishi Liu: Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China
Bangsheng Wu: Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China
Weiwei Shen: Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China
Tongyao You: Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China
Suzhen Liang: Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China
Qiang Dong: State key Laboratory of Brain Function and Disorders and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
Jintai Yu: Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China; State key Laboratory of Brain Function and Disorders and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China; Correspondence to: Department of Neurology, Huashan Hospital, State Key Laboratory of Brain Function and Disorders and MOE Frontiers Center for Brain Science, Fudan University, No. 12 Middle Wulumuqi Road, Shanghai 200040, China.
Yanxin Zhao: Department of Neurology, Shanghai Eighth People's Hospital, 8 Caobao Road, Shanghai, China; Correspondence to: Department of Neurology, Shanghai Eighth People's Hospital, 8 Caobao Road, Shanghai 200030, China.
Mei Cui: Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China; State key Laboratory of Brain Function and Disorders and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China; Correspondence to: Department of Neurology, Huashan Hospital, State Key Laboratory of Brain Function and Disorders and MOE Frontiers Center for Brain Science, Fudan University, No. 12 Middle Wulumuqi Road, Shanghai 200040, China.

DOI: https://doi.org/10.1016/j.phrs.2025.107908
Journal volume & issue: Vol. 219
p. 107908

Abstract

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Neuroinflammation is a key feature of Parkinson's disease (PD), characterized by activated microglia and the conversion of astrocytes into the neurotoxic phenotype, exacerbating the neuroinflammation. In PD, microglia critically drive neurotoxic reactive astrocytes (A1, A1-like, or neuroinflammatory reactive astrocytes)—though the underlying mechanisms remain elusive. Given the established role of exosomes as critical intercellular messengers, we investigated whether microglia-derived exosomes contribute to neurotoxic astrocyte transformation. Our findings demonstrate that microglial depletion via PLX3397 significantly attenuated α-synuclein pre-formed fibrils (α-syn PFF)-induced neurotoxic reactive astrocytes. Crucially, purified microglial exosomes alone proved sufficient to drive astrocyte polarization toward the neurotoxic phenotype in mice. Complementary approaches—exosome depletion from microglial supernatants and GW4869-mediated exosome secretion blockade—convergently alleviated neurotoxic astrocytic phenotype conversion, verifying exosome-dependent mechanisms. Mechanistically, PFF-activated microglial exosomes carried proinflammatory factors and toxic α-syn oligomers. These cargo components exacerbated neuroinflammation through induction of the neurotoxic astrocyte phenotype and direct mediation of neuronal damage. Critically, upon intrastriatal injection, these exosomes were internalized by astrocytes in the striatum and substantia nigra, triggering concurrent astrocyte proliferation and neurotoxic phenotypic conversion. Additionally, we identify Peli1, an E3 ubiquitin ligase selectively enriched in microglia, as a key regulator of microglia activation and exosome release. Peli1 inhibition alleviates microglia activation and neurotoxic astrocyte conversion. Moreover, our findings reveal a feedback loop between neurotoxic astrocytes and microglia, wherein neurotoxic astrocytes upregulate Peli1 expression in microglia, further promoting neuroinflammation. This study highlights microglial exosomes in regulating neurotoxic astrocyte activation and identifies Peli1 as a novel target for PD intervention.

Published in Pharmacological Research

ISSN: 1096-1186 (Online)
Publisher: Elsevier
Country of publisher: United Kingdom
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.sciencedirect.com/journal/pharmacological-research

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