Different effects of soluble and aggregated amyloid β42 on gene/protein expression and enzyme activity involved in insulin and APP pathways

J Neural Transm (Vienna). 2013 Jan;120(1):113-20. doi: 10.1007/s00702-012-0852-5. Epub 2012 Jul 11.

Abstract

Although Alzheimer's dementia (AD) is not characterised any longer simply as the accumulation and deposition of amyloid beta (Aβ) peptides and hyperphosphorylation of tau proteins within the brain, excessive Aβ(42) deposition is still considered to play a major role in this illness. Aβ are able to adopt many differently aggregate forms, including amyloid fibrils as well as nonfibrillar structures (soluble Aβ(42) oligomers). It is not well-established that which Aβ(42) state is most responsible for AD or why. We wanted to verify which effects Aβ(42) oligomers and aggregated peptides have on gene expression, protein level and enzyme activity of insulin and amyloid precursor protein (APP) pathways in vitro. Human neuroblastoma cells (SH-SY5Y) were treated with varying concentrations of soluble and aggregated Aβ(42). Treatment effects on β-secretase (BACE), glycogen synthase kinase 3α (GSK3α), glycogen synthase kinase 3β (GSK3β), phosphatidylinositol-3 kinase (PI-3K), insulin-degrading enzyme (IDE), insulin-receptor substrate 1 (IRS1), insulin receptor (INSR) and monoamine oxidase B (MAO-B) were investigated via quantitative-PCR, western blot, ELISA and enzyme activity assay. We could find different effects of soluble and aggregated peptides especially on gene/protein expression of GSK3β and INSR and on GSK3β and MAO-B activity. Soluble peptides showed significant effects leading to increased gene expression and protein amount of GSK3β and to decreased level of gene and protein expression of INSR. MAO-B activity was enhanced after treatment with aggregated peptides and strongly inhibited after soluble Aβ(42) treatment. Our data might provide insights into selective effects of specific forms of Aβ(42) aggregates in AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / pharmacology*
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Glycogen Synthase Kinase 3 / genetics
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Insulin / genetics
  • Insulin / metabolism*
  • Insulysin
  • Monoamine Oxidase / genetics
  • Monoamine Oxidase / metabolism
  • Neuroblastoma / pathology
  • Peptide Fragments / pharmacology*
  • Phosphatidylinositol 3-Kinases
  • RNA, Messenger / metabolism
  • Receptor, Insulin / genetics
  • Receptor, Insulin / metabolism

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Insulin
  • Peptide Fragments
  • RNA, Messenger
  • amyloid beta-protein (1-42)
  • Monoamine Oxidase
  • Phosphatidylinositol 3-Kinases
  • Receptor, Insulin
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Glycogen Synthase Kinase 3
  • Amyloid Precursor Protein Secretases
  • Insulysin