Single cell biology to analyse cellular heterogeneity in the response to amyloid plaques in Alzheimer’s Disease

Microglial activation and neuroinflammation are crucial in the pathogenesis of Alzheimer’s disease. However, studies in mouse models and human postmortem samples have yielded divergent results regarding transcriptional programs in microglia elicited by exposure to amyloid‐b pathology. Here, we investigate 127,000 single cell expression profiles of human microglia isolated freshly from a xenotransplantation model for AD. Human microglia adopt a different, more complex spectrum of cell states than mouse microglia. Besides a disease associated (DAM) profile, human microglia show a pronounced HLA‐response related to antigen presentation in response to amyloid‐b plaques, which is absent in mouse. Furthermore, oligomeric amyloid‐β present in this model induces a distinctive pro‐inflammatory CRM response characterized by the expression of cytokines and chemokines, also not seen in mice. TREM2 and APOE polymorphisms modulate the response of microglia to amyloid‐b plaques, much less to oligomeric Aβ. In conclusion, human microglia mount a multipronged ARM response to amyloid pathology in Alzheimer’s disease. This implies that therapeutic strategies targeting microglia need to analyse carefully the effect on these different cell states some of which seem protective.