The cyanobacterial neurotoxin β-N-methylamino-L-alanine prevents addition of heparan sulfate to glypican-1 and increases processing of amyloid precursor protein in dividing neuronal cells

Research output: Contribution to journalArticle

Abstract

The neurotoxin β-N-methylamino-L-alanine replaces L-serine in proteins and produces Alzheimer-like pathology. In proteoglycans, e.g. glypican-1, this should preclude substitution with heparan sulfate chains. Reduced release of heparan sulfate should increase β-secretase activity and processing of amyloid precursor protein. Cultured cells were treated with β-N-methylamino-L-alanine during the growth-phase and the effect on heparan sulfate substitution and amyloid precursor protein processing was evaluated using antibodies specific for heparan sulfate, the N- and C-termini of the C-terminal fragment of β-cleaved amyloid precursor protein, and amyloid beta followed by immunofluorescence microscopy, flow cytometry or SDS-PAGE. Mouse fibroblasts, N2a neuroblastoma cells and human neural stem cells released less heparan sulfate when grown in the presence of β-N-methylamino-L-alanine. Cells expressing a recombinant, anchor-less glypican-1 secreted heparan sulfate-deficient glypican-1. There was increased processing of amyloid precursor protein in N2a cells when grown in the presence of the neurotoxin. The degradation products accumulated in cytoplasmic clusters. Secretion of amyloid beta increased approx. 3-fold. Human neural stem cells also developed cytoplasmic clusters containing degradation products of amyloid precursor protein. When non-dividing mouse N2a cells or cortical neurons were exposed to β-N-methylamino-L-alanine there was no effect on heparan sulfate substitution in glypican-1 or on amyloid precursor protein processing.

Details

Authors
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology

Keywords

  • Alzheimer's disease, Amyloid precursor protein, Glypican-1, Heparan sulfate, Neuronal cells, Neurotoxin
Original languageEnglish
Pages (from-to)172-181
Number of pages10
JournalExperimental Cell Research
Volume379
Issue number2
Publication statusPublished - 2019
Publication categoryResearch
Peer-reviewedYes