title: The rise and fall of insulin signaling in Alzheimer's disease.
abstract: The prevalence of both diabetes and Alzheimer's disease (AD) are reaching epidemic proportions worldwide. Alarmingly, diabetes is also a risk factor for Alzheimer's disease. The AD brain is characterised by the accumulation of peptides called Aβ as plaques in the neuropil and hyperphosphorylated tau protein in the form of neurofibrillary tangles within neurons. How diabetes confers risk is unknown but a simple linear relationship has been proposed whereby the hyperinsulinemia associated with type 2 diabetes leads to decreased insulin signaling in the brain, with downregulation of the PI3K/AKT signalling pathway and its inhibition of the major tau kinase, glycogen synthase kinase 3β. The earliest studies of post mortem AD brain tissue largely confirmed this cascade of events but subsequent studies have generally found either an upregulation of AKT activity, or that the relationship between insulin signaling and AD is independent of glycogen synthase kinase 3β altogether. Given the lack of success of beta-amyloid-reducing therapies in clinical trials, there is intense interest in finding alternative or adjunctive therapeutic targets for AD. Insulin signaling is a neuroprotective pathway and represents an attractive therapeutic option. However, this incredibly complex signaling pathway is not fully understood in the human brain and particularly in the context of AD. Here, we review the ups and downs of the research efforts aimed at understanding how diabetes modifies AD risk.
authors.affiliation: Redox Biology, The University of Sydney, Sydney, NSW,, 2006, Australia.
authors.forename: B
authors.initials: B
authors.lastname: Chami
authors.affiliation: Neuropathology Group, Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, NSW, 2006, Australia.
authors.forename: A J
authors.initials: AJ
authors.lastname: Steel
authors.affiliation: Department of Neurology, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI, USA.|Department of Neurosurgery, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI, USA.|Department of Pathology, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: De La Monte
authors.affiliation: Neuropathology Group, Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, NSW, 2006, Australia. g.sutherland@sydney.edu.au.
authors.forename: Greg T
authors.identifier: 0000-0003-2493-9736
authors.initials: GT
authors.lastname: Sutherland
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D038362:Glycogen Synthase Kinase 3
keywords: Alzheimer’s disease; Glycogen synthase kinase 3beta; Insulin signaling pathway; Type 2 diabetes