In addition AMPK reduces protein synthesis and stimulates ap

In addition, AMPK reduces protein synthesis and stimulates apoptotic and autophagic pathways through the inhibition of the mechanistic target of rapamycin (mTOR), which regulates cellular metabolic homeostasis, insulin secretion, insulin resistance, autophagy and apoptosis (Maiese, 2016). mTOR is the central component of the protein complexes mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 is activated by insulin, growth factors and nutrients, resulting in increased translation. Insulin induces mTORC1 activity by inhibiting the tumor suppressor complex (TSC1/TSC2), which is an endogenous mTORC1 repressor (Fig. 1). In contrast, AMPK inhibits mTORC1 signaling by phosphorylating TSC1/TSC2 as well as phosphorylating and promoting the dissociation of the protein raptor, which is one of the mTORC1 components (Foster, 2012, Hasenour et al., 2013, Steinberg and Kemp, 2009). During regular exercise, AMPK mediates fat oxidation by inhibiting ACC and decreases both lipogenesis and protein synthesis through the inhibition of SREBP-1c and mTORC1, respectively. Interestingly, autophagy is involved in the degradation and removal of aggregated proteins, the impairment of which causes neuronal cell death. The inhibition of constitutive autophagy leads to neurodegeneration and mTORC1 has been implicated as having a detrimental role in the autophagic process associated with several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis (ALS) (Kiriyama and Nochi, 2015). Consequently, AMPK could emerge as a therapeutic target for these neurodegenerative diseases also by acting as a modulator of the autophagic process (Fig. 2). AMPK is also thought to play an important role in LGX818 receptor and insulin resistance and, consequently, the pathogenesis of type 2 diabetes, nonalcoholic fatty liver disease and hypertension. An association has been found between the activation of inflammatory genes and a decrease in AMPK activity due to elevated oxidative stress in adipose tissue of insulin-resistant patients (Xu et al., 2012). Moreover, AMPK activation in patients with obesity or type 2 diabetes is attenuated after exercise, indicating that chronic metabolic syndrome may result in AMPK dysregulation (Sriwijitkamol et al., 2007). Clinical studies indicate that higher glucose levels are associated with an increased risk of dementia, even at the lowest end of the glucose spectrum among individuals who have not been diagnosed with diabetes (Crane et al., 2013). Other studies provide evidence of an association between insulin resistance in type 2 diabetes and an increased incidence of both dementia (Qiu et al., 2014) and Alzheimer's disease (Schrijvers et al., 2010). Recently, elegant studies have demonstrated that patients with preclinical Alzheimer's exhibit dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes (Kapogiannis et al., 2015). All these data demonstrate that degeneration in the nervous system may be the result of impaired cellular metabolism similar to what occurs in patients with diabetes mellitus. Direct and indirect AMPK activators have been proposed as novel therapeutic tools for metabolic syndrome, type 2 diabetes, atherosclerosis and cancer. The direct AMPK activators [thienopyridone (A-769662), benzimidazole (compound 911), compound-13 and salicylate derivatives] lead to activation, possibly through a direct interaction with a specific subunit of AMPK. Indirect AMPK activators (metformin, thiazolidinediones, polyphenols and α-lipoic acid) cause changes in the cellular AMP/ATP ratio by inhibiting complex I of the mitochondrial respiratory chain or mitochondrial F1F0-ATPase/ATP synthase (Kim et al., 2016, Luengo et al., 2014). However, little is known regarding potential AMPK activators, such as anti-inflammatory drugs, in neurodegenerative disorders.