RT Journal Article SR Electronic T1 Prevention of Alzheimer Pathology by Blocking Neuregulin Signaling on Microglia JF eneuro JO eNeuro FD Society for Neuroscience SP ENEURO.0422-23.2023 DO 10.1523/ENEURO.0422-23.2023 VO 10 IS 11 A1 Liu, Jianguo A1 Geraghty, Joseph R. A1 Schram, Sarah A1 Cropper, Haley C. A1 Lei, Justin A1 Loeb, Jeffrey A. A1 Song, Fei YR 2023 UL http://www.eneuro.org/content/10/11/ENEURO.0422-23.2023.abstract AB Plaque formation, microglial activation, and synaptic loss are pathologic hallmarks of Alzheimer’s disease; however, removing plaques has had little clinical benefit. Here, we show that neuregulin-1, a glial growth factor, induces inflammatory cytokines and promotes phagocytic activity in vitro and augments microglial activation and plaque formation in 5XFAD Alzheimer’s mice. Brain-specific targeting of neuregulin-1 by intraventricular delivery of a novel neuregulin-1 fusion protein antagonist, GlyB4, significantly alters microglial morphology and function to a nonpathogenic morphology in early-stage 5XFAD mice and prevents plaques from forming. Once plaques have already formed, GlyB4 reduces new plaque formation and prevents synaptic loss. Selective, targeted disruption of neuregulin-1 signaling on brain microglia with GlyB4 could be a novel “upstream” approach to slow or stop disease progression in Alzheimer’s disease.