title: 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 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.
authors.forename: Domenico
authors.initials: D
authors.lastname: Nuzzo
authors.forename: Pasquale
authors.initials: P
authors.lastname: Picone
authors.forename: Sara
authors.initials: S
authors.lastname: Baldassano
authors.forename: Luca
authors.initials: L
authors.lastname: Caruana
authors.forename: Elisa
authors.initials: E
authors.lastname: Messina
authors.forename: Antonella
authors.initials: A
authors.lastname: Marino Gammazza
authors.forename: Francesco
authors.initials: F
authors.lastname: Cappello
authors.forename: Flavia
authors.initials: F
authors.lastname: Mulè
authors.affiliation: Institute of Biomedicine and Molecular Immunology CNR, via Ugo La Malfa 153, 90146 Palermo, Italy. marta.dicarlo@ibim.cnr.it.
authors.forename: Marta
authors.initials: M
authors.lastname: Di Carlo
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D058227:Amyloidogenic Proteins / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D016022:Case-Control Studies; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013997:Time Factors
chemical_list: D058227:Amyloidogenic Proteins; D016207:Cytokines; D007328:Insulin; D011972:Receptor, Insulin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D053829:Amyloid Precursor Protein Secretases