AbstractBackgroundUnder normal conditions, amyloid (Aβ) is released extracellularly by neurons as a neuroprotective molecule while healthy microglia ingest and degrade Aβ to maintain a balance between production and clearance. One of the hallmarks of Alzheimer’s Disease (AD) is the presence of plaques composed of aggregated, fibrillar amyloid beta (Aβ) that usually precedes the deposition of Tau. Aggregated Aβ can be degraded within healthy microglia largely by autophagy. Most vacuoles containing Aβ acquire the autophagy marker LC3 in primary WT microglia but not in AD microglia. It is still unclear why microglia in the AD brain fail to clear Aβ. Microglia in human AD brain sections and in the 5XFAD (AD) mouse model congregate around Aβ plaques and express high levels of miR‐17 which we found targets autophagy effectors.MethodWe examined the effect of targeting microRNA miR‐17 in vitro and in vivo using designed mannose‐labeled nanoparticles for the delivery of antagomirs exclusively to microglia.ResultIsolated primary microglia from adult AD mouse fail to degrade Aβ in comparison to wild‐type (WT) microglia. The expression of autophagy effectors Nbr1, Atg5 and Atg7, which are targets of miR‐17, are significantly reduced in AD mouse microglia (CD11b+) and not in CD11b− fraction which contains astrocytes and neuronal cells. This is the first report of significant increase of miR‐17 in the microglia of AD humans and mice. The increased expression of miR‐17 in AD microglia reduces the expression of autophagy effectors leading to defective autophagy in AD microglia. We show that reducing the expression of miR‐17 using specific antagomir (Anti‐17) in AD microglia in vitro, is sufficient to significantly improve their ability to degrade Aβ. Importantly, we successfully injected live AD mice with Anti‐17 enclosed within mannose‐labeled nanoparticles (Man‐NPs) which specifically target the mannose receptor mainly expressed on microglia. This delivery method significantly and explicitly reduced the elevated expression of miR‐17 in microglia, reduced the expression of Aβ in the brain and reduced hyperactivity behavior in live AD mice.ConclusionTogether, we describe Man‐NPs for the delivery of antagomirs specifically to microglia. We show that targeting miR‐17 in microglia is sufficient to prevent AD pathobiology.