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.