Figure 2.

Potential mechanisms of irisin in Alzheimer’s disease (AD). Recent studies have shown that irisin, which is a hormone stimulated via physical exercise derived from the precursor protein fibronectin type III domain-containing protein 5 (FNDC5), is reduced in the brains and cerebrospinal fluid (CSF) of humans with AD. The AMP-activated protein kinase (AMPK) is a key pathway in autophagy. Irisin can modulate this pathway by activating the AMPK pathway and inhibiting mTOR, thus leading to the increase in autophagy and the clearance of amyloid and toxic aggregates in the brain. Irisin can decrease pro-apoptotic Bad, Bax and caspase-3, and caspase 9 while increasing anti-apoptotic proteins Bcl-2 and Bcl-xl through the ERK signaling pathway. Irisin demonstrates the inhibition of the necroptotic signaling pathway through increasing BDNF (which increases neurogenesis), mitigating the impact of HMGB1 and suppressing tumor necrosis factor (TNF-α) mRNA expression. It can also inhibit p38, STAT3, and NFκB, reducing neuroinflammation.