Neuroprotective effects of physical activity on the brain: a closer look at trophic factor signaling

Abstract

While the relationship between increased physical activity and cognitive ability has been conjectured for centuries, only recently have the mechanisms underlying this relationship began to emerge. Convergent evidence suggests that physical activity offers an affordable and effective method to improve cognitive function in all ages, particularly the elderly who are most vulnerable to neurodegenerative disorders. In addition to improving cardiac and immune function, physical activity alters trophic factor signaling and, in turn, neuronal function and structure in areas critical for cognition. Sustained exercise plays a role in modulating anti-inflammatory effects and may play a role in preserving cognitive function in aging and neuropathological conditions. Moreover, recent evidence suggests that myokines released by exercising muscles affect the expression of brain-derived neurotrophic factor synthesis in the dentate gyrus of the hippocampus, a finding that could lead to the identification of new and therapeutically important mediating factors. Given the growing number of individuals with cognitive impairments worldwide, a better understanding of how these factors contribute to cognition is imperative, and constitutes an important first step toward developing non-pharmacological therapeutic strategies to improve cognition in vulnerable populations.

Keywords: FNDC5; Irisin; Val66Met; brain-derived neurotrophic factor; myokines; neurotrophins; physical activity.

Figure 1

Schematic representation of BDNF release, binding to TrkB receptors, and downstream events following internalization. BDNF dimers bind to TrkB receptors and cause autophosphorylation of tyrosine residues on the cytoplasmic domain of TrkB receptors, generating docking sites for several intracellular proteins. In turn, the activation of the TrkB receptors facilitate interactions with Shp2, Shc, and PLC-γmolecules and effectuates the signaling cascades such as PLC/PKC, PI3K/Akt, Ras/Erk, AMPK/ACC and NFB pathways. Signaling pathways involved in BDNF-TrkB interactions include: (1) PLC-γ1 signaling: Phosphorylated TrkB receptors bind to PLC-γ1 and lead to its’ activation. PLC-γ1 hydrolyses Phosphatidylinositol (4,5) to generate IP3 and DAG. While IP3 promotes release of Ca²⁺ from internal stores, DAG stimulates DAG-regulated protein kinase C isoforms. (2) Ras-MAP/erk signaling: Phosphorylation of Trk receptors provides a recruitment site for binding of the PTB domain of the adaptor protein, Shc. Shc recruits the adaptor protein, Grb2, and complexes with SOS, an exchange factor for Ras (and Rac). Activated Ras stimulates signaling through several downstream pathways, including those mediated by PI3-kinases, Raf, and p38MAP kinase. (3) PI-3 kinase signaling: Phosphatidylinositides are generated by PI3-kinase and activate phosphatidylinositide-dependent protein kinase (PDK-1). PDK-1 activates the protein kinase Akt (also known as PKB), which then phosphorylates several proteins important in promoting cell survival.

Figure 2

Schematic representation of possible mechanisms by which val66met substitution in BDNF leads to failed activity-dependent release of BDNF. Val66met substitution alters the dynamics of interaction between BDNF and two important proteins: (1) Sortilin, which is involved in intracellular sorting and pro-neurotrophin signaling. Val66met substitution leads to reduction of BDNF interaction with this protein, which results in mis-sorting into the constitutive secretory pathway instead of activity-dependent release. (2) Translin is a highly conserved protein involved in mRNA transport. An exon found in all BDNF mRNA splice variants contains a specific translin-binding region, which is essential for appropriate BDNF mRNA dendritic targeting. It has been shown that val66met substitution diminishes BDNF mRNA interaction with translin, which leads to reduced translocation of BDNF mRNA to dendrites (Published from Sanchez et al., 2011).

Figure 3

The relationship between the total volume of the hippocampus and age in met and non-met carriers. Using a polynomial fitting curve, we found a significant correlation (r = −0.447, P = 0.0150) between age and the volume of the hippocampus in met carriers. No such correlation was found in non-met carriers (r = −0.178, P = 0.2639). Furthermore, the slope of the regression in the hippocampal volume of met carriers (slope = −0.038) was twice the value of the slope of regression in non-met carriers (slope = −0.016; Published from Sanchez et al., 2011).

Figure 4

Schematic representation of mechanisms by which increased physical activity leads to improved cognitive function. The figure depicts the two compartments alongside the blood brain barrier and the bidirectional relationship of BNDF between central and peripheral compartments. For instance, muscles, liver, and immune cells in the periphery impose a significant influence on the brain, particularly on the DG of the hippocampus. Conversely, BDNF has the ability to easily cross the BBB and influence multiple mechanisms in the periphery. The fact that TrkB receptors have been found in the spinal cord, DRGs, muscles, intestines, and kidneys suggests that BDNF can exert multiple regulatory effects on both sides of the BBB. Through co-activation of PGC1α and ERRα, physical activity induces the production of FNCD5. Following cleavage by a protease, FNDC5 is cleaved into irisin, which has the ability to cross the BBB and induce BDNF gene expression in the hippocampus. Notably, it has also been shown that high concentrations of IGF-1 are released by the liver and can, in turn, improve neurogenesis in the DG and induce BDNF gene expression.