The activation of fibroblast growth factor receptor 1 provides therapeutic benefit in a mouse model of Alzheimer's disease

Abstract

Alzheimers disease (AD) is a neurodegenerative disease that is characterized by the accumulation of amyloid plaque and neurofibrillary tangles, ultimately impairing multiple cognitive domains. Both plaques and tangles cause neuronal damage and stimulate inflammatory responses in glial cells. The fibroblast growth factor receptor 1 (FGFR1)-mediated signaling pathways support the function of damaged neurons and modulate inflammatory response. The FGFR1 agonists, including Fibroblast growth factor 1 (FGF1) and FG loop peptide (FGL), have been implicated in multiple disease therapy. Whether FGFR1 agonists can improve pathology and cognitive function in AD remains unknown. Here, we showed that administration of FGF1 and FGL to the AD mouse model reversed spatial memory impairment, enhanced neurogenesis, suppressed reactive astrogliosis, and restricted dystrophic neurite. However, only FGF1 treatment reduced the deposition of senile plaque. In microglial culture studies, FGF1 improves the phagocytosis ability of microglia, which contributes to the clearance of plaques. Together, our findings suggested that FGFR1 agonists alleviate pathology and cognitive impairment via immunomodulatory and improve neuronal health in the AD mouse model. HighlightsFGFR1 agonists alleviate memory deficits in AD mice. FGFR1 agonists increase adult neurogenesis and limit dystrophic neurites in AD mice. FGFR1 agonists increase plaque-associated microglia in vivo and promote phagocytosis in vitro.