Modulation of the Astrocyte-Neuron Lactate Shuttle System contributes to Neuroprotective action of Fibroblast Growth Factor 21

Abstract

A viewpoint considering Alzheimer's disease (AD) as “type 3 diabetes” emphasizes the pivotal role of dysfunctional brain energy metabolism in AD. The hormone fibroblast growth factor 21 (FGF21) is a crucial regulator in energy metabolism; however, our understanding of the therapeutic potential and mechanisms underlying the effect of FGF21 on neurodegeneration of AD is far from complete. Methods: To further elucidate the effect of FGF21 on AD-related neurodegeneration, we used APP/PS1 transgenic mice to assess the effects of FGF21 on memory dysfunction, amyloid plaque pathology and pathological tau hyperphosphorylation. We also established an in vitro system to mimic astrocyte-neuron communication and an in vivo model of acute injury. Based on the in vivo and in vitro models, we analyzed the neuroprotective actions of FGF21 and pathways related to astrocyte-neuron communication and further focused on the astrocyte-neuron lactate shuttle system. Results: Here, we report that FGF21 can ameliorate Alzheimer-like neurodegeneration in APP/PS1 transgenic mice. We detected defects in the astrocyte-neuron lactate shuttle system in the in vivo and in vitro models of AD and identified FGF21 as a neuroprotective molecule that can rescue these deficits. Administration of FGF21 can alleviate memory dysfunction, amyloid plaque pathology and pathological tau hyperphosphorylation, and the function of FGF21 in neurodegeneration is mediated in part by monocarboxylate transporters (MCTs). In vivo evidence also suggests that FGF21 acts centrally in mice to exert its effects on neurodegeneration and energy metabolism via its regulation of MCTs. Conclusions: These results suggest that FGF21 alters metabolic parameters to mediate its neuroprotective functions. Modulation of the astrocyte-neuron lactate shuttle system can be one of the most efficient strategies for FGF21 in Alzheimer-like degeneration and contributes to improvements in brain metabolic defects and amyloid β-induced cytotoxicity. Our findings provide insights into the mechanisms underlying the effects of FGF21 on neurodegeneration and brain energy metabolism and suggest that FGF21 may have therapeutic value in the treatment of AD and other neurodegenerative diseases.

RGC-32 Acts as a Hub to Regulate the Transcriptomic Changes Associated With Astrocyte Development and Reactive Astrocytosis

“…We turned our attention to the genes that were significantly up-regulated only in WT astrocytes and generated a full list of the 209 genes ( Supplementary File 1 ). The first two genes in this category were fibroblast growth factor 21 (Fgf21), which encodes a growth factor with neuroprotective effects ( 29 ), and interleukin 11 (Il-11), which encodes a member of the IL-6 family of cytokines with a potential role in driving astrocyte differentiation through the activation of STAT3 ( 30 ). RGC-32 itself was the 14 th most up-regulated gene (Rgcc), a result that was not surprising because TGF-β is a potent inductor of its expression ( 17 ).…”

Physical Exercise-Induced Myokines in Neurodegenerative Diseases

“…Meanwhile, FGF21 induced by calorie restriction reduced tau phosphorylation through the mTOR axis, and tau pathology was ameliorated by FGF21 in Aβ-treated SH-SY5Y cells [205,207]. Furthermore, astrocyteneuron lactate shuttle (ANLS) was implicated in decreased tau phosphorylation by FGF21 in a transwell co-culture system with C6 astrocytes and PC12 neurons [208].…”

“…Although not many studies have been conducted on the effect of FGF21 on NDs, several recent preclinical studies have shown that FGF21 has a neuroprotective effect in ND models by affecting several signaling pathways. In both in vivo and in vitro AD models, FGF21 has shown anti-inflammatory and antioxidant effects, and prevented amyloid plaque formation, neurofibrillary tangle formation, and neurodegeneration [205][206][207][208]. Moreover, FGF21 treatment led to alleviated dopaminergic neuron loss, improved mitochondrial function and behavioral ability, and decreased inflammation in PD models [209][210][211][212].…”

Peptides Derived from Growth Factors to Treat Alzheimer’s Disease

“…FGFs, such as FGF-2 and FGF-21, have been shown to be beneficial to treat AD hallmarks ( Table 1 ) [ 112 , 219 ]. While no difference was detected in the levels of LMW FGF-2 between AD patients and age-matched healthy controls, the expression of HMW FGF-2 isoforms was drastically decreased in AD patients [ 219 ].…”