FGFR1 agonists alleviate pathology and cognitive impairment in an Alzheimer's disease mouse model

Wei-Chien Hung; Wei-Chun Sun; Tzu-Ching Su; Yi-Jung Lee; Irene Han-Juo Cheng

doi:10.1016/j.expneurol.2025.115357

FGFR1 agonists alleviate pathology and cognitive impairment in an Alzheimer's disease mouse model

Exp Neurol. 2025 Jun 23:392:115357. doi: 10.1016/j.expneurol.2025.115357. Online ahead of print.

Authors

Wei-Chien Hung¹, Wei-Chun Sun², Tzu-Ching Su³, Yi-Jung Lee⁴, Irene Han-Juo Cheng⁵

Affiliations

¹ Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Taiwan International Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, Taiwan.
² Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Taiwan International Graduate Program in Interdisciplinary Neuroscience, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, Taiwan.
³ Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
⁴ Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Division of Neurology, Department of Medicine, Taipei City Hospital Renai Branch, Taipei, Taiwan.
⁵ Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Taiwan International Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, Taiwan; Taiwan International Graduate Program in Interdisciplinary Neuroscience, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, Taiwan; Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan. Electronic address: ihjcheng@nycu.edu.tw.

PMID: 40562341
DOI: 10.1016/j.expneurol.2025.115357

Abstract

Alzheimer's disease (AD) is the leading cause of dementia, characterized by the buildup of amyloid plaques and neurofibrillary tangles, which lead to neuronal damage and trigger inflammatory responses in glial cells. The fibroblast growth factor receptor 1 (FGFR1)-mediated signaling pathways support the function of damaged neurons and modulate the inflammatory response. The FGFR1 agonists, including Fibroblast growth factor 1 (FGF1) and FG loop peptide (FGL), have been implicated in multiple disease therapies. However, whether FGFR1 agonists can improve pathology and cognitive function in AD remains unknown. This study showed that administration of FGF1 and FGL to the AD mouse model reversed spatial memory impairment, enhanced neurogenesis, suppressed reactive astrogliosis, and restricted dystrophic neurites. However, only FGF1 treatment reduced the deposition of senile plaque. In microglial culture studies, FGF1 improves the phagocytosis ability of microglia, but this effect is blocked by the FGFR1-specific inhibitor. Together, our findings suggested that FGFR1 agonists alleviate pathological and cognitive impairments in the AD mouse model.

Keywords: Alzheimer's disease; Amyloid β; FGF1; FGFR1 agonist; FGL; Fibroblast growth factor receptor 1.