Amyloid precursor protein dimerisation reduces neurite outgrowth

Luan Luu, Giuseppe D. Ciccotosto, Laura J. Vella, Lesley Cheng, Laila C. Roisman, Gerhard Multhaup, Andrew F. Hill, Lisa Marie Munter, Roberto Cappai*

*Corresponding author for this work

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The amyloid precursor protein (APP) undergoes extensive metabolism, and its transport and proteolytic processing can be modulated by its ability to form a homodimer. We have investigated the functional consequences of stabilised APP dimer expression in cells by studying the engineered dimerisation of the APP L17C (residue 17 in Aβ sequence) construct, which is associated with a 30% increase in APP dimer expression, on APP’s neurite outgrowth promoting activity. Overexpression of APP L17C in SH-SY5Y cells decreased neurite outgrowth upon retinoic acid differentiation as compared to overexpressing APP WT cells. The APP L17C phenotype was rescued by replacing the APP L17C media with conditioned media from APP WT cells, indicating that the APP L17C mutant is impairing the secretion of a neuritogenic promoting factor. APP L17C had altered transport and was localised in the endoplasmic reticulum. Defining the molecular basis of the APP L17C phenotype showed that RhoA GTPase activity, a negative regulator of neurite outgrowth, was increased in APP L17C cells. RhoA activity was decreased after APP WT conditioned media rescue. Moreover, treatment with the RhoA inhibitor, Y27632, restored a wild-type morphology to the APP L17C cells. Small RNAseq analysis of APP L17C and APP WT cells identified several differentially expressed miRNAs relating to neurite outgrowth. Of these, miR-34a showed the greatest decrease in expression. Lentiviral-mediated overexpression of miR-34a rescued neurite outgrowth in APP L17C cells to APP WT levels and changed RhoA activation. This study has identified a novel link between APP dimerisation and its neuritogenic activity which is mediated by miR-34a expression.

Original languageEnglish
Pages (from-to)13-28
Number of pages16
JournalMolecular Neurobiology
Volume56
Issue number1
DOIs
Publication statusPublished - 1 Jan 2019
Externally publishedYes

Keywords

  • Amyloid precursor protein
  • Dimerisation
  • Function
  • microRNA
  • Neurite
  • RhoA

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  • Cite this

    Luu, L., Ciccotosto, G. D., Vella, L. J., Cheng, L., Roisman, L. C., Multhaup, G., ... Cappai, R. (2019). Amyloid precursor protein dimerisation reduces neurite outgrowth. Molecular Neurobiology, 56(1), 13-28. https://doi.org/10.1007/s12035-018-1070-4