title: Lipoic acid improves neuronal insulin signalling and rescues cognitive function regulating VGlut1 expression in high-fat-fed rats: Implications for Alzheimer's disease.
abstract: The concept of central insulin resistance and dysfunctional insulin signalling in sporadic Alzheimer's disease (AD) is now widely accepted and diabetes is recognized as one of the main risk factors for developing AD. Moreover, some lines of evidence indicated that VGlut1 is impaired in frontal regions of AD patients and this impairment is correlated with the progression of cognitive decline in AD. The present work hypothesizes that ketosis associated to insulin resistance could interfere with the normal activity of VGlut1 and its role in the release of glutamate in the hippocampus, which might ultimately lead to cognitive deficits. High fat diet (HFD) rats showed memory impairments and both peripheral (as shown by increased fasting plasma insulin levels and HOMA index) and hippocampal (as shown by decreased activation of insulin receptor, IRS-1 and pAkt) insulin pathway alterations, accompanied by increased ketone bodies production. All these effects were counteracted by α-lipoic acid (LA) administration. VGlut1 levels were significantly decreased in the hippocampus of HFD rats, and this decrease was reversed by LA. Altogether, the present results suggest that HFD induced alterations in central insulin signalling could switch metabolism to produce ketone bodies, which in turn, in the hippocampus, might lead to a decreased expression of VGlut1, and therefore to a decreased release of glutamate and hence, to the glutamatergic deficit described in AD. The ability of LA treatment to prevent the alterations in insulin signalling in this model of HFD might represent a possible new therapeutic target for the treatment of AD.
authors.affiliation: Department of Pharmacology and Toxicology, University of Navarra, 31008 Pamplona, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Rodriguez-Perdigon
authors.affiliation: Department of Pharmacology and Toxicology, University of Navarra, 31008 Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Spain.
authors.forename: Maite
authors.initials: M
authors.lastname: Solas
authors.affiliation: IdiSNA, Navarra Institute for Health Research, Spain; Department of Food Sciences and Physiology, University of Navarra, 31008 Pamplona, Spain; Centre for Nutrition Research, University of Navarra, 31008 Pamplona, Spain.
authors.forename: Maria Jesús
authors.initials: MJ
authors.lastname: Moreno-Aliaga
authors.affiliation: Department of Pharmacology and Toxicology, University of Navarra, 31008 Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Spain. Electronic address: mariaja@unav.es.
authors.forename: Maria Javier
authors.initials: MJ
authors.lastname: Ramirez
mesh_terms: D000544:Alzheimer Disease / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D003071:Cognition / Q000187:drug effects*; D004041:Dietary Fats / Q000009:adverse effects* / Q000494:pharmacology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000097:blood*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D008297:Male; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D008063:Thioctic Acid / Q000494:pharmacology*; D050598:Vesicular Glutamate Transport Protein 1 / Q000096:biosynthesis*
chemical_list: D004041:Dietary Fats; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; C493466:Slc17a7 protein, rat; D050598:Vesicular Glutamate Transport Protein 1; D008063:Thioctic Acid; D051057:Proto-Oncogene Proteins c-akt
keywords: Cognitive deficits; High-fat-diet; Insulin; Ketone bodies; VGlut1