Ischemic injury triggers a protective microglial phenotype in models of Aβ pathology

Microglia are highly plastic cells that are capable of integrating subsequent insults. As the majority of Alzheimer’s Disease (AD) patients also show cerebrovascular pathology, we here aimed to dissect the interactions between AD and ischemic brain injury on the microglial response to amyloid beta (Aβ) pathology. Surprisingly, we find that ischemic stroke in the presence of cerebral β-amyloidosis results in the generation of a novel neuroprotective microglial phenotype. These microglia drive a rapid accumulation of highly dense Aβ plaques that exhibit a relatively benign nature and are strikingly similar to Aβ plaques observed in patients that are resilient to AD pathology. Thus, our data do not only highlight the impact of a co-morbid state of brain ischemia and Aβ pathology on the microglial phenotype but also identify novel molecular pathways that may serve to promote beneficial microglial functions in AD.