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이상환Sang Hwan Lee

서울대학교 의과대학

Exp. Mol. Med., May 01 2025, | https://doi.org/10.1038/s12276-025-01450-z Microglia-driven inflammation induces progressive tauopathies and synucleinopathies

Sang Hwan Lee ^1,2, Eun-Jin Bae^1,2, Sung Jun Park ¹ and Seung-Jae Lee^1,2,3,*

¹Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
²Neuroscience Research Institute, Medical Research Center, Seoul National University, Seoul, Republic of Korea.
³Convergence Research Center for Dementia, Medical Research Center, Seoul National University, Seoul, Republic of Korea.

^*Corresponding author: correspondence to Seung-Jae Lee

Abstract

Alzheimer's disease and Parkinson's disease are characterized by distinct types of abnormal protein aggregates within neurons. These aggregates are known as neurofibrillary tangles and Lewy bodies, which consist of tau and α-synuclein, respectively. As the diseases progress, these aggregates spread from one cell to another, causing protein pathology to affect broader regions of the brain. Another notable characteristic of these diseases is neuroinflammation, which occurs when microglia become activated. Recent studies have suggested that inflammation may contribute to the formation and propagation of protein aggregates. However, it remains unclear whether microglia-driven inflammation can initiate and propagate different proteinopathies and associated neuropathology in neurodegenerative diseases. Here, using single-cell RNA sequencing, we observed that microglia exposed to α-synuclein or tau underwent changes in their characteristics and displayed distinct types of inflammatory response. The naive mice that received these microglial cell transplants developed both tauopathy and synucleinopathy, along with gliosis and inflammation. Importantly, these pathological features were not limited to the injection sites but also spread to other regions of the brain, including the opposite hemisphere. In conjunction with these pathological changes, the mice experienced progressive motor and cognitive deficits. These findings conclusively demonstrate that microglia-driven inflammation alone can trigger the full range of pathological features observed in neurodegenerative diseases, and that inflammation-induced local neuropathology can spread to larger brain regions. Consequently, these results suggest that microglia-driven inflammation plays an early and pivotal role in the development of neurodegenerative diseases. The transplantation of microglia activated by αSyn or tau proteins into the brains of naive mice resulted in the formation of synucleinopathy, tauopathy, gliosis, neuroinflammation and behavioral abnormalities. Activated microglia displayed alterations in subclusters as well as the corresponding feature genes.

논문정보

형식Research article
게재일2025년 05월 (BRIC 등록일 2025-05-07)
연구진국내 연구진
분야 의약학 > 신경의학

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