## 6 Irisin: A New Bridge between Exercise and Cognitive Functions  
As mentioned above, irisin exerts its role at a systemic level, including the CNS [46; 47]. Since 2016, several findings on irisin's impacts on cognitive functions have been made. These findings suggest that the beneficial effects of PE in counteracting memory degradationare mediated by irisin from a peripheral and central origin. In turn, the impactor irisin on cognition is to a large extent elicited by the induction of the neurothrombin BDNF. In general, BDNF is essential for brain development due to its actions in neuronal survival, differentiation, and migration, and in exerting a role in dendritic arborization and in regulating synapse genesis and plasticity. Consequently, BDNF is fundamental for hippocampal function and learning [112; 113; 114]. It has been widely described that higher levels of BDNF have a beneficial effect on many cognitive processes, such as verbal, recognition, spatial, and episodic memory [115; 116]. In humans, mutation in the BDNF gene (i.e., Val66 Met) is associated with a decreased level of BDNF, with the affected subjects characterized by a higher level of mood disturbances, such as increased anxiety and depression, alterations in episodic memory, and reduced volume in specific regions of the brain [117; 118]. BDNF is related to the positive effect of PE on CNS, in particular acting on the above cited neuronal survival/differentiation, and synaptic plasticity [48; 49; 53]. In humans, circulating BDNF was successfully associated with PE, cognitive performance and hippocampal volume [51; 52]. In a several studies, [PERSON] and colleagues suggested that the blockage of BDNF signaling with a specific antibody (ant-TrkB) significantly reduced the improvement in acquisition and retention during spatial memory tasks induced by PE; this inhibition was paralleled by a decrease in expression of synaptic proteins [119; 120]. In accordance, other studies suggested associations between PE, circulating BDNF levels and the hippocampal volume [121; 122], whose systemic decline is associated with advanced age [123]. Notably, the activation of the FNDC5/irisin system in the brain is an important inductor of BDNF. The overexpression of FNDC5 in primary cortical neurons increases BDNF expression, and in a similar manner the BDNF expression is significantly abrogated by RNAi-mediated knockdown of the FNDC5 gene [124]. An animal model showed that the irisin precursor FNDC5 could mediate beneficial CNS effects of endurance exercise by upregulating BDNF expression in the hippocampus [8]. Accordingly, the above-mentioned human polymorphism of BDNF, Val66 Met, was shown to affect both BDNF and FNDC5 expression in the brain after PE [125]. Nevertheless, in a mouse model of AD, the neurogenesis mediated by PE in the hippocampus was associated with similar induction of expression of BDNF and FNDC5, facilitating improvement in cognitive functions [126]. [PERSON] et al., (2015), suggested that endurance PE elevates systemic irisin levels, inducing the expression of FNDC5 in the hippocampus by PGC-1a, and leading to BDNF expression. This process culminates in neurogenesis induction in this region [127]. In two recent studies, [PERSON] and coworkers investigated the relationship between the potential alteration of the FNDC5/irisin system and AD. They showed that silencing FNDC5 with specific small hairpin RNA in a mouse brain, determined the loss of long-term potential (LTP) at hippocampal level. A similar loss of LTP was induced in a model of AD obtained by injecting amyloid-\(\beta\) oligomers (A\(\beta\)Os) and causing memory and behavioral defects. The injection of the recombinant irisin in the glycosylated form was able to reverse these processes on LTP loss and behavioral alterations. In an additional approach, the same authors used an adenovirus expressing FNDC5 into the brain, injecting ABOs after six days, and obtaining analog recovery of animals.