title: Unraveling the molecular mechanisms behind the metabolic basis of sporadic Alzheimer's disease.
abstract: Peripheral insulin resistance is associated with hyperinsulinemia, which may be associated with brain insulin deficiency that is characteristic of sporadic Alzheimer's disease (sAD). Oxidative insult, which is the result of insulin associated disordered brain energy metabolism, is a significant early event in the pathological cascade of sAD. Aggregation of disease-specific proteins such as amyloid-beta and tau may act as a compensatory response against the oxidative insult at the early periods. In the later stages, oxidative stress stimulates c-Jun N-terminal kinase (JNK) activation. The deficient insulin signaling is ultimately linked to protein kinase B (Akt) pathway and subsequently glycogen synthase kinase-3 (GSK3) and forkhead transcription factors (FOXO). Peripheral insulin resistance related intense interactions between JNK, GSK3, FOXO factors, and p53, which may lead to apoptotic neuronal death, are outlined in a postulate. In light of this postulate, the importance of detailed knowledge of these common physiological processes for the opportunities of treatment that could prevent or reduce the onset of sAD is discussed as well.
authors.affiliation: Erol Institute for the disorders of energy metabolism, Silivri-Istanbul, Turkey. eroladnan@hotmail.com
authors.forename: Adnan
authors.initials: A
authors.lastname: Erol
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D051858:Forkhead Transcription Factors / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases; D008659:Metabolic Diseases / Q000150:complications*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D051858:Forkhead Transcription Factors; D007328:Insulin; D048031:JNK Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3