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Prevention of Alzheimer Pathology by Blocking Neuregulin Signaling on Microglia.

ABSTRACT: 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.

SUBMITTER: Liu J

PROVIDER: S-EPMC10644371 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Prevention of Alzheimer Pathology by Blocking Neuregulin Signaling on Microglia.

Liu Jianguo J Geraghty Joseph R JR Schram Sarah S Cropper Haley C HC Lei Justin J Loeb Jeffrey A JA Song Fei F

eNeuro 20231110 11

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 <i>in vitro</i> 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 antag ...[more]

PMID: 37903620

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