Investigation of the effects and mechanisms of endogenous deletion of FGF21 on cognitive functions.

Abstract

Cognitive impairment is characterized by reduced cognitive abilities in one or more areas such as language, memory, and reasoning. It is a common problem in various neurological diseases and the aging process, seriously affecting people's quality of life and overall health. Fibroblast growth factor 21 (FGF21), a hormone regulating glucose/lipid metabolism and energy homeostasis, exhibits neuroprotective properties. To investigate the impact and mechanism of endogenous deletion of FGF21 on cognitive function, FGF21 knockout mice and wild-type mice were used. Different behavioral paradigms were used to study the effects of FGF21 on the cognitive behavior of mice. Morphological changes were observed by Nissl and HE staining, and RNA sequencing was performed to explore potential links between FGF21 and cognitive impairment-related diseases. Behavioral and morphological analyses demonstrated that FGF21 knockout mice exhibited deficits in learning and memory, anxiety-like behaviors, and neuronal degeneration. Transcriptomic profiling revealed that FGF21 deficiency altered multiple neuroprotective processes, including metabolism and synaptic transmission. These deficits may be mediated through downregulation of the PPAR signaling pathway, thereby affecting cognitive function. This research indicates that endogenous FGF21 deletion disrupts basic cognitive and emotional behaviors of mice, which may accelerate the development of cognitive impairment-related diseases (including Alzheimer's disease, vascular cognitive impairment, frontotemporal dementia, dementia with Lewy bodies), and suggests FGF21 as a potential therapeutic target for these diseases.