Xenografted human microglia in response to Alzheimer's disease Aβ pathology.

Background: Neuroinflammation is a pathological hallmark of Alzheimer's disease (AD). Murine studies have revealed that mouse microglia can adopt several cell states in response to disease insults. However, single‐nuclei RNA sequencing studies have found divergent results when recalling those cell states in human post‐mortem tissue. Method: To overcome this limitation, we have sequenced 127,000 single cell human microglia isolated from an AD xenotransplantation model. Result: In response to plaques, human microglia can adopt several cell states including a disease‐associated microglia (DAM) and an antigen‐presenting response (HLA). When reacting to Aβ soluble aggregates, human microglia produces a pro‐inflammatory response cytokine response (CRM). TREM2 and APOE polymorphisms affect the development of the DAM‐HLA response, suggesting an important role of this response in AD. Conclusion: Overall, this multi‐faceted response to amyloid pathologies highlights a complex scenario where these distinct phenotypes might influence the outcome on the disease. [ABSTRACT FROM AUTHOR]