Therapeutic potential of exercise-hormone irisin in Alzheimer's disease

Abstract

Irisin is a myokine that is generated by cleavage of the membrane protein fibronectin type III domain-containing protein 5 (FNDC5) in response to physical exercise. Studies reveal that irisin/FNDC5 has neuroprotective functions against Alzheimer's disease, the most common form of dementia in the elderly, by improving cognitive function and reducing amyloid-β and tau pathologies as well as neuroinflammation in cell culture or animal models of Alzheimer's disease. Although current and ongoing studies on irisin/FNDC5 show promising results, further mechanistic studies are required to clarify its potential as a meaningful therapeutic target for alleviating Alzheimer's disease. We recently found that irisin treatment reduces amyloid-β pathology by increasing the activity/levels of amyloid-β-degrading enzyme neprilysin secreted from astrocytes. Herein, we present an overview of irisin/FNDC5's protective roles and mechanisms against Alzheimer's disease.

Figure 1

Neuroprotective effects of exercise-induced irisin in AD brain. During exercise, the PGC1α-dependent myokine, FNDC5, undergoes cleavage into irisin and is subsequently secreted from muscle. The extracellular chaperone Hsp90 serves as the activating factor that facilitates the “opening” of the integrin αV/β5 receptor, which enables high-affinity binding of irisin. In the AD brain, irisin was found to reduce amyloid and tau pathologies, mitigate neuroinflammation, and consequently enhance cognitive function. Created with BioRender.com. Aβ: Amyloid-β; APOE: apolipoprotein E; APP_swe/PS1_ΔE9 or PS1_M146L: double transgenic mouse model overexpressing amyloid precursor protein (APP) Swedish and presenilin 1 (PS1) ΔE9 or M146L mutations; C3: complement C3; ERK: extracellular signal-regulated kinase; FNDC5: fibronectin type III domain-containing protein 5; GFAP: glial fibrillary acidic protein; Hsp90α: heat shock protein 90α; hTau: transgenic mouse model overexpressing human tau; IL-6: interleukin-6; LTP: long-term potentiation; NF-κB p65: nuclear factor kappa B p65; Pgc1α: peroxisome proliferator-activated receptor-gamma coactivator 1-alpha; pTau: phosphorylated tau; Ser: serine; STAT3: signal transducer and activator of transcription 3; TNFα: tumor necrosis factor alpha; 3D-AD: three-dimensional cell culture model of Alzheimer’s disease; 5×FAD: transgenic mouse model overexpressing familial Alzheimer’s disease mutations.