FGF21 restores metabolic function in Alzheimer's disease via activation of PI3K/Akt signaling

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, oxidative stress, and mitochondrial dysfunction. Fibroblast growth factor 21 (FGF21) has demonstrated neuroprotective effects, though its role in AD pathogenesis remains unclear. The present study aims to discover neuroprotective effects of FGF21 in AD by examining its influence on energy metabolism and neuronal survival through the PI3K/Akt signaling pathways.

In vivo experiments were performed using 5×FAD transgenic mice, while in vitro assays utilized amyloid beta 1-42 (Aβ1-42)-treated SH-SY5Y cells and a co-culture system of primary rat astrocytes with SH-SY5Y cells. To evaluate the effects of FGF21 modulation, we performed both gain- and loss-of-function experiments and assessed outcomes using behavioral testing, histopathological and ultrastructural analyses, oxidative stress and mitochondrial function assays, and Western blotting. The involvement of the PI3K/Akt/mTOR pathway was explored using the PI3K inhibitor LY294002.

Both in vivo and in vitro AD models exhibited reduced FGF21 expression. FGF21 downregulation impaired PI3K/Akt signaling, induced neuronal apoptosis, and disrupted metabolic homeostasis. Loss of FGF21 resulted in cognitive and metabolic dysfunction in AD mice. Conversely, FGF21 overexpression activated PI3K/Akt signaling, suppressed neuronal apoptosis, and restored metabolic functions in AD models.

FGF21 alleviates AD-related cognitive impairment and restores metabolic function by activating the PI3K/Akt pathway.