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

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

Volume: 12 Issue: 8

Author(s): Domenico Nuzzo, Pasquale Picone, Sara Baldassano, Luca Caruana, Elisa Messina, Antonella Marino Gammazza, Francesco Cappello, Flavia Mulè and Marta Di Carlo

Affiliation:

Keywords: Adipokines, Alzheimer’s disease, gene expression, inflammation, insulin resistance, mitochondrial dysfunction, obesity.

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 Aβ₄₀/Aβ₄₂ 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 Aβ₄₀/Aβ₄₂ 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.

Cite this article as:

Nuzzo Domenico, Picone Pasquale, Baldassano Sara, Caruana Luca, Messina Elisa, Gammazza Marino Antonella, Cappello Francesco, Mulè Flavia and Carlo Di Marta, Insulin Resistance as Common Molecular Denominator Linking Obesity to Alzheimer’s Disease, Current Alzheimer Research 2015; 12 (8) . https://dx.doi.org/10.2174/1567205012666150710115506