Different effects of soluble and aggregated amyloid ß42 on gene/protein expression and enzyme activity involved in insulin and APP pathways.

ABSTRACT

Although Alzheimer's dementia (AD) is not characterised any longer simply as the accumulation and deposition of amyloid beta (Aß) peptides and hyperphosphorylation of tau proteins within the brain, excessive Aß(42) deposition is still considered to play a major role in this illness. Aß are able to adopt many differently aggregate forms, including amyloid fibrils as well as nonfibrillar structures (soluble Aß(42) oligomers). It is not well-established that which Aß(42) state is most responsible for AD or why. We wanted to verify which effects Aß(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 Aß(42). Treatment effects on ß-secretase (BACE), glycogen synthase kinase 3α (GSK3α), glycogen synthase kinase 3ß (GSK3ß), 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 GSK3ß and INSR and on GSK3ß and MAO-B activity. Soluble peptides showed significant effects leading to increased gene expression and protein amount of GSK3ß 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 Aß(42) treatment. Our data might provide insights into selective effects of specific forms of Aß(42) aggregates in AD.