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.

No abstract

No abstract

No abstract

In Alzheimer's disease (AD), neuronal thread protein (NTP) accumulates in cortical neurons and colocalizes with phospho- tau-immunoreactive cytoskeletal lesions that correlate with dementia. To generate additional information about the potential role of NTP in AD, we characterized its expression and regulation in human SH-Sy5y neuronal cells. Quantitative real-time reverse transcription-polymerase chain reactin and Western blot analysis demonstrated prominent insulin, moderate insulin-like growth factor, type 1 (IGF-1) and minimal nerve growth factor stimulation of NTP expression. In addition, NTP protein was more stable and it progressively accumulated in cells that were stimulated with insulin for 24 or 48 h. Metabolic labeling and phospho-amino acid analysis demonstrated phosphorylation of NTP on Serine residues, 30-60 min after insulin or IGF-1 stimulation, when glycogen synthase kinase 3beta (GSK-3beta) activity would no longer have been suppressed. Kinase inhibitor and in vitro phosphorylation studies demonstrated a role for GSK-3beta in the positive regulation of NTP expression and phosphorylation. Coimmunoprecipitation studies demonstrated physical interactions between NTP and tau or microtubule-associated protein 1b (MAP-1b), and ubiquitin immunoreactivity in NTP immunoprecipitates. In summary, these studies showed that (i) NTP expression is regulated at the level of transcription by insulin and IGF-1 stimulation; (ii) NTP is phosphorylated by GSK-3beta; (iii) NTP can physically interact with tau and MAP-1b and (iv) NTP-MAP complexes are ubiquitinated. The results suggest a functional role for NTP in relation to the turnover or processing of neuronal cytoskeletal proteins, attributes that may be modulated by insulin/IGF-1-mediated signaling.

No abstract

No abstract