Insulin Resistance as Common Molecular Denominator Linking Obesity to Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) is an aging-related multi-factorial disorder to which metabolic factors contribute at what has canonically been considered a centrally mediated process. Although the exact underlying mechanisms are still unknown, obesity is recognized as a risk factor for AD and the condition of insulin resistance seems to be the link between the two pathologies. Using mice with high fat diet (HFD) obesity we dissected the molecular mechanisms shared by the two disorders. Brains of HFD fed mice showed elevated levels of APP and Aβ 40 /Aβ 42 together with BACE, GSK3β and Tau proteins involved in APP processing and Aβ accumulation. Immunofluorescence, Thioflavin T staining experiments, confirmed increased Aβ generation, deposition in insoluble fraction and plaques formation in both the hippocampus and the cerebral cortex of HFD mice. Presence of Aβ 40 and Aβ 42 in the insoluble fraction was also shown by ELISA assay. Brain insulin resistance was demonstrated by reduced presence of insulin receptor (IRs) and defects in Akt-Foxo3a insulin signaling. We found reduced levels of phospho-Akt and increased levels of Foxo3a in the nuclei of neurons where proapototic genes were activated. Dysregulation of different genes related to insulin resistance, especially those involved in inflammation and adipocytokines synthesis were analyzed by Profiler PCR array. Further, HFD induced oxidative stress, mitochondrial dysfunction and dynamics as demonstrated by expression of biomarkers involved in these processes. Here, we provide evidence that obesity and AD markers besides insulin resistance are associated with inflammation, adipokine dyshomeostasis, oxidative stress and mitochondrial dysfunction, all mechanisms leading to neurodegeneration.

Cdk5–Foxo3 axis: initially neuroprotective, eventually neurodegenerative in Alzheimer's disease models

“…Finally, our in vivo data also supports increased levels and increased nuclear localization of Foxo3 in mouse brains upon Cdk5 activation, further underscoring the significance of this pathway in Alzheimer's disease pathogenesis. A recent study indeed showed increased levels of Foxo3 in the nuclei of neurons in mice with high fat diets where proapototic genes were activated (Nuzzo et al, 2015). Most importantly, these mice exhibited several Alzheimer's disease phenotypes including increased levels of APP, Aβ(1-40) and Aβ(1-42) along with BACE and tau proteins, which further exemplifies the significance of Foxo3 signaling in Alzheimer's disease pathogenesis.…”

Mitochondrial dysfunction and cell death in neurodegenerative diseases through nitroxidative stress

“…Other risk factors can be coronary artery disease, high blood pressure (hypertension), stroke, serum cholesterol contents (Proitsi et al, 2014), etc. Recent studies suggest that metabolic syndromes, such as diabetes and obesity with insulin resistance, also play an important role in causing sporadic AD (de la Monte and Tong, 2009, 2014; Nuzzo et al, 2015). Diets containing high fat with or without high fructose/sucrose and sedentary life style may represent another risk factor that contributes to the cognitive decline in animal models (Agrawal et al, 2015; Chang et al, 2014; Liu et al, 2014b; McNeilly et al, 2012; Morrison et al, 2010).…”

“…Recently obesity was shown as another risk factor for AD in mice fed a high fat diet (HFD). In the brains of HFD-fed mice, the levels of APP and Aβ40/Aβ42 were significantly elevated in both hippocampal and cortical regions (Nuzzo et al, 2015). In addition, the decreased number of insulin receptors and the inhibition of Akt-Foxo3 signaling were observed.…”

GLP2: an underestimated signal for improving glycaemic control and insulin sensitivity

“…In mice fed a high-fat diet (HFD), endogenous GLP2 acts as a protective factor against the dysregulation of glucose metabolism that occurs in HFD-fed mice because GLP2 (3-33) chronic treatment exacerbates glucose metabolism disorders . It is well known that in C57BL/6J mouse model, a chronic exposure to HFD induces obesity and a progressive deterioration of metabolic control, characterized by hyperglycaemia, hyperinsulinaemia and peripheral and central insulin resistance (Surwit et al 1988, Ahrén et al 1997, Lee et al 1995, Nuzzo et al 2015. Mice after 10 weeks on HFD have greater mass gain compared with standard diet-fed mice, show hyperglycaemia, an impaired glycaemic response following intraperitoneal glucose load, high plasma insulin level after glucose load, increased pancreas weight and β cell expansion, but not insulin resistance.…”