Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease – is this type 3 diabetes?

• Published in: Journal of Alzheimer's disease Vol. 7; no. 1; pp. 63 - 80
• Main Authors: Steen, Eric, Terry, Benjamin M., J. Rivera, Enrique, Cannon, Jennifer L., Neely, Thomas R., Tavares, Rose, Xu, X. Julia, Wands, Jack R., de la Monte, Suzanne M.
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.02.2005
• Subjects: Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - physiopathology; Brain - immunology; Brain - metabolism; Cerebral Cortex - immunology; Cerebral Cortex - metabolism; Diabetes Mellitus - genetics; Diabetes Mellitus - immunology; Diabetes Mellitus - metabolism; DNA Primers - genetics; Glycogen Synthase Kinase 3 - genetics; Glycogen Synthase Kinase 3 - immunology; Glycogen Synthase Kinase 3 - metabolism; Humans; Hypothalamus - immunology; Hypothalamus - metabolism; Immunohistochemistry; Immunoprecipitation; Insulin - immunology; Insulin - metabolism; Insulin-Like Growth Factor I - genetics; Insulin-Like Growth Factor I - immunology; Insulin-Like Growth Factor I - metabolism; Insulin-Like Growth Factor II - genetics; Insulin-Like Growth Factor II - immunology; Insulin-Like Growth Factor II - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Signal Transduction - physiology; tau Proteins - metabolism; insulin signaling; insulin gene expression; growth factor receptors; glycogen synthase kinase; real time RT-PCR; diabetes; Alzheimer's disease; central nervous system
• ISSN: 1387-2877; 1875-8908
• DOI: 10.3233/JAD-2005-7107

The neurodegeneration that occurs in sporadic Alzheimer's disease (AD) is consistently associated with a number of characteristic histopathological, molecular, and biochemical abnormalities, including cell loss, abundant neurofibrillary tangles and dystrophic neurites, amyloid-β deposits, increased activation of pro-death genes and signaling pathways, impaired energy metabolism/mitochondrial function, and evidence of chronic oxidative stress. The general inability to convincingly link these phenomena has resulted in the emergence and propagation of various heavily debated theories that focus on the role of one particular element in the pathogenesis of all other abnormalities. However, the accumulating evidence that reduced glucose utilization and deficient energy metabolism occur early in the course of disease, suggests a role for impaired insulin signaling in the pathogenesis of AD. The present work demonstrates extensive abnormalities in insulin and insulin-like growth factorm typer I and II (IGF-I and IGF-II) signaling mechanisms in brains with AD, and shows that while each of the corresponding growth factors is normally made in central nervous system (CNS) neurons, the expression levels are markedly reduced in AD. These abnormalities were associated with reduced levels of insulin receptor substrate (IRS) mRNA, tau mRNA, IRS-associated phosphotidylinositol 3-kinase, and phospho-Akt (activated), and increased glycogen synthase kinase-3β activity and amyloid precursor protein mRNA expression. The strikingly reduced CNS expression of genes encoding insulin, IGF-I, and IGF-II, as well as the insulin and IGF-I receptors, suggests that AD may represent a neuro-endocrine disorder that resembles, yet is distinct from diabetes mellitus. Therefore, we propose the term, "Type 3 Diabetes" to reflect this newly identified pathogenic mechanism of neurodegeneration.