Author:
Gerrits Emma,Brouwer Nieske,Kooistra Susanne M.,Woodbury Maya E.,Vermeiren Yannick,Lambourne Mirjam,Mulder Jan,Kummer Markus,Möller Thomas,Biber Knut,Dunnen Wilfred F. A. den,De Deyn Peter P.,Eggen Bart J. L.,Boddeke Erik W. G. M.
Abstract
AbstractAlzheimer’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.
Publisher
Springer Science and Business Media LLC
Subject
Cellular and Molecular Neuroscience,Clinical Neurology,Pathology and Forensic Medicine
Cited by
208 articles.
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