Journal Article

Microglia-driven inflammation induces progressive tauopathies and synucleinopathies

Lee, Sang Hwan, Bae, Eun-Jin, Park, Sung Jun, Lee, Seung-Jae

2025

Overview

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. Microglia activation initiates tau and α-synuclein spread Alzheimer’s disease (AD) and Parkinson’s disease (PD) are common brain disorders that cause memory and movement problems. Both diseases involve harmful protein buildups in the brain. Researchers explored how inflammation in the brain might contribute to these diseases. They focused on microglia, which are immune cells in the brain that can cause inflammation. In their study, they activated microglia using proteins linked to AD and PD. These activated microglia were then injected into mice brains. The study found that these microglia caused signs of brain damage like those seen in AD and PD, including protein buildups and inflammation. The researchers used various methods, including single-cell RNA sequencing, to analyze changes in the microglia. The results suggest that inflammation driven by microglia might play a key role in the early stages of neurodegenerative diseases. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group,생화학분자생물학회
• Subject: 13/1 / 13/51 / 14/19 / 14/34 / 38/39 / 631/378/1689/1283 / 631/378/1689/1718 / 631/378/1689/364 / 631/80/304 / 64/60 / 96/21 / alpha-Synuclein - immunology / alpha-Synuclein - metabolism / Alzheimer Disease - diagnosis / Alzheimer Disease - immunology / Alzheimer Disease - pathology / Alzheimer's disease / Animals / Artificial intelligence / Biomedical and Life Sciences / Biomedicine / Brain / Brain injury / Cell Line, Tumor / Cerebral Cortex - immunology / Cerebral Cortex - metabolism / Cerebral Cortex - pathology / Disease / Disease Models, Animal / Disease Progression / Gene Expression Regulation - immunology / Gliosis / Humans / Inflammation / Lewy bodies / Lewy Bodies - immunology / Lewy Bodies - metabolism / Male / Medical Biochemistry / Mice / Mice, Inbred C57BL / Microglia / Microglia - immunology / Microglia - metabolism / Microglia - pathology / Microglia - transplantation / Molecular Medicine / Movement disorders / Neurodegenerative diseases / Neurofibrillary tangles / Neurofibrillary Tangles - immunology / Neurofibrillary Tangles - metabolism / Neuroinflammatory Diseases - diagnosis / Neuroinflammatory Diseases - immunology / Neuroinflammatory Diseases - pathology / Neuropathology / Parkinson Disease - diagnosis / Parkinson Disease - immunology / Parkinson Disease - pathology / Parkinson's disease / Primary Cell Culture / Protein Aggregates - immunology / Proteins / Single-Cell Gene Expression Analysis / Stem Cells / Stereotaxic Techniques / Synuclein / Tau protein / tau Proteins - immunology / tau Proteins - metabolism / Transplants / 생화학