Inflammation and Oxidative Stress: The Molecular Connectivity between Insulin Resistance, Obesity, and Alzheimer’s Disease

Figure 2

Molecular mechanisms linking insulin resistance with neurodegeneration. Obesity is characterized by chronic low-grade inflammation, which impacts all tissues and organs. Inflammatory cytokines bind to their receptors (1) activating the nuclear factor-kappaB (NF-κB/IκBα) pathway, which stimulates a proinflammatory condition (2). Nutrient imbalance may also activate inflammatory pathways and DNA damage, adversely impacting redox regulation (via glutathione peroxidase (GPx); glutathione (GSH); and oxidised glutathione (GSSG) levels) and so promoting oxidative stress (3). β-cell metabolism and ATP production are affected by nutrient imbalance via glycolytic dysfunction and reduced activation of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) reducing pyruvate (PYR) generation but promoting β-oxidation (4). As a result of the metabolic dysfunction, superoxide and subsequently hydrogen peroxide generation (which can combine with nitric oxide, NO, to create peroxynitrite, an example of RNS) may occur due to compromised mitochondrial electron transport chain, ETC, and action, and so reducing ATP synthesis (5). All these processes impact endoplasmic reticulum (ER) stress, leading to a reduction in the ability to secrete insulin (6). High circulating levels of lipids and glucose and chronic inflammation increase amyloid beta (Aβ) aggregation, which together with low insulin reduce the transport and utilisation of glucose in the brain (7) via impairment in insulin signalling (8), including the negative regulator of glycogen synthase kinase 3 (GSK3). Activated GSK3 is associated with tau hyperphosphorylation (9). The vicious cycle mediated by ROS/RNS and Aβ may eventually result in enzyme inhibition (e.g., alpha-enolase (ENO1), malate dehydrogenase (MDH), ATP synthase, and GAPDH), lowering ATP generation, which together with tau promotes neuronal loss (10). Protein kinase B (AKT); fructose bisphosphate enolase (FBE); fructose bisphosphate aldolase (FBA); calcium (Ca²⁺); iron (Fe²⁺); glucose transporters (GLUT); hydrogen peroxide (H₂O₂); interleukin- (IL-) 1 and interleukin- (IL-) 6; insulin receptor substrate (IRS); Janus kinase (JNK); potassium (K⁺); nitric oxide (NO); anion superoxide (); hydroxyl radical (OH⁻); peroxynitrite (ONOO⁻); pyruvate dehydrogenase kinase, isozyme 1 (PDK1); pancreatic and duodenal homeobox 1 (PDX-1); Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K); superoxide dismutase (SOD); tumour necrosis factor alpha (TNF-α); ubiquitin-proteasome system (UPS).