Liver-derived FGF21 contributes to protection against Alzheimer’s disease pathogenesis

Objectives Fibroblast growth factor 21 (FGF21) is a liver-derived hormone that regulates systemic glucose and lipid homeostasis. Previous work indicates that FGF21 attenuates Amyloid β (Aβ) toxicity in mouse and cellular models of Alzheimer’s disease (AD). Although predominantly secreted by the liver, FGF21 crosses the blood–brain barrier and binds receptors in the hippocampus and other brain regions. We investigated whether sustained, liver-derived FGF21 modulates AD pathogenesis and confers neuroprotection against hallmark pathology. Methods At 8-weeks of age, 3xTg-AD mice received an intravenous dose of a liver-specific expression plasmid (pLIVE-FGF21-HA) to induce sustained hepatic FGF21 expression. Five months later, we assessed cognition (novel object recognition, Y-maze) and synaptic function by hippocampal electrophysiology. Aβ plaque burden was quantified by immunostaining with Aβ-specific antibody. Neuroinflammation was assessed via immunofluorescence against the astrocytic marker, glial fibrillary acidic protein (GFAP). Brain penetration of liver-expressed HA-tagged FGF21 was confirmed by hemagglutinin (HA) tag immunofluorescence. Results Our results show that sustained hepatic FGF21 expression reduces Aβ pathology and restores synaptic and cognitive functions in 3xTg-AD mice. Conclusions These data support exploring FGF21 as a therapeutic candidate for AD and other neurodegenerative disorders. Targeting FGF21 could offer a novel way to slow disease progression and illuminate mechanisms of AD pathogenesis.