期刊
ACTA NEUROPATHOLOGICA
卷 141, 期 5, 页码 681-696出版社
SPRINGER
DOI: 10.1007/s00401-021-02263-w
关键词
Microglia; Alzheimer’ s disease; Single-nucleus RNA sequencing; Amyloid-β Tau
资金
- Graduate School of Medical Sciences of the University of Groningen
- Flemish Institute for Technological Research (VITO)
- Research Foundation Flanders (FWO) [12Z1620N]
- Stichting MS Research
- Alzheimer Nederland
This study conducted single-nuclei RNA sequencing on Alzheimer's disease (AD)-related human microglia, revealing two distinct expression profiles associated with pathology. These findings shed light on the role of microglia in AD and offer new targets for microglia-specific therapeutic strategies.
Alzheimer's disease (AD) is the most prevalent form of dementia and is characterized by abnormal extracellular aggregates of amyloid-beta and intraneuronal hyperphosphorylated tau tangles and neuropil threads. Microglia, the tissue-resident macrophages of the central nervous system (CNS), are important for CNS homeostasis and implicated in AD pathology. In amyloid mouse models, a phagocytic/activated microglia phenotype has been identified. How increasing levels of amyloid-beta and tau pathology affect human microglia transcriptional profiles is unknown. Here, we performed snRNAseq on 482,472 nuclei from non-demented control brains and AD brains containing only amyloid-beta plaques or both amyloid-beta plaques and tau pathology. Within the microglia population, distinct expression profiles were identified of which two were AD pathology-associated. The phagocytic/activated AD1-microglia population abundance strongly correlated with tissue amyloid-beta load and localized to amyloid-beta plaques. The AD2-microglia abundance strongly correlated with tissue phospho-tau load and these microglia were more abundant in samples with overt tau pathology. This full characterization of human disease-associated microglia phenotypes provides new insights in the pathophysiological role of microglia in AD and offers new targets for microglia-state-specific therapeutic strategies.
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