1. Distinct amyloid-β and tau-associated microglia profiles in Alzheimer’s disease
- Author
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Nieske Brouwer, Thomas Möller, Jan Mulder, Maya E. Woodbury, Emma Gerrits, Peter Paul De Deyn, Knut Biber, Wilfred F. A. den Dunnen, Markus P. Kummer, Yannick Vermeiren, Erik Boddeke, Mirjam Lambourne, Susanne M. Kooistra, Bart J. L. Eggen, Molecular Neuroscience and Ageing Research (MOLAR), Translational Immunology Groningen (TRIGR), and Restoring Organ Function by Means of Regenerative Medicine (REGENERATE)
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Amyloid ,Central nervous system ,Population ,tau Proteins ,Biology ,Pathology and Forensic Medicine ,s disease ,Amyloid-β ,Cellular and Molecular Neuroscience ,Alzheimer Disease ,Single-nucleus RNA sequencing ,mental disorders ,medicine ,Extracellular ,Humans ,Amyloid-β ,education ,Alzheimer’ ,Aged ,Aged, 80 and over ,education.field_of_study ,Original Paper ,Amyloid beta-Peptides ,Microglia ,Brain ,Phenotype ,Pathophysiology ,Nutritional Biology ,medicine.anatomical_structure ,nervous system ,Female ,Neurology (clinical) ,Human medicine ,Tau ,Alzheimer’s disease ,Homeostasis - Abstract
Alzheimer’s disease (AD) is the most prevalent form of dementia and is characterized by abnormal extracellular aggregates of amyloid-β 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-β 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-β plaques or both amyloid-β 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-β load and localized to amyloid-β 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. Supplementary Information The online version contains supplementary material available at 10.1007/s00401-021-02263-w.
- Published
- 2021