Prevention of Alzheimer pathology by blocking neuregulin signaling on microglia.

Abstract

Plaque formation, microglial activation, and synaptic loss are pathological hallmarks of Alzheimer's disease, however, removing plaques have 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 non-pathogenic 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.Significance StatementMicroglia-associated neuroinflammation is a major hallmark of Alzheimer's disease. Here, we show that neuregulin1 (NRG1), an important neuron-glial signaling factor in development, induces microglial activation and promotes pathological changes in the 5XFAD mouse model of Alzheimer's disease. Inhibition of NRG1 using a targeted NRG1 antagonist called GlyB4 blocks NRG1 receptor activation in microglia, reduces Amyloid β plaque formation, and prevents synaptic loss. While NRG1 clearly has important functions at other sites in the nervous system, excessive NRG1 signaling in microglia leads to pathological neuroinflammation and neurodegeneration. Selective disruption of NRG1 signaling in microglia using GlyB4 could be a novel approach to block disease progression in patients with Alzheimer's disease.