Benzolactam (BL) enhances sAPP secretion in fibroblasts and in PC12 cells

Dolores Ibarreta, Miriam Duchén, Dawei Ma, Lixin Qiao, Alan P. Kozikowski, René Etcheberrigaray

Research output: Contribution to journalArticle

Abstract

ACTIVATION of protein kinase C is known to favor the α-secretase processing of the Alzheimer's disease (AD) amyloid precursor protein (APP), resulting in the generation of non-amyloidogenic soluble APP (sAPP). Consequently, the relative secretion of amyloidogenic Aβ1-40 and Aβ(1- 42(3)) is reduced. This is particularly relevant since fibroblasts and other cells expressing APP and presenilin AD mutations secrete increased amounts of total Aβ and/or increased ratios of Aβ(1-42(3))/Aβ1-40. Interestingly, PKC defects have been found in AD brain (α and β isoforms) and in fibroblasts (α isoform) from AD patients. Here, we use a novel PKC activator (benzolactam, BL) with improved selectivity for the α, β and γ isoforms to enhance sAPP secretion in fibroblasts from AD patients and in PC12 cells. Incubation (2 h) of AD fibroblasts with BL (1 and 10 μM) resulted in significant increases of sAPP secretion over basal levels. sAPP secretion in BL-treated AD cells was also slightly higher compared to control BL-treated fibroblasts, which only showed significant increases of sAPP secretion after treatment with 10 αM BL. Staurosporine (a PKC inhibitor) eliminated the effects of BL in both control and AD fibroblasts. BL and a related compound (LQ12) also caused an ~3-fold sAPP secretion in PC12 cells. The use of a novel and possibly non-tumorigenic PKC activator may prove useful to favor non-amyloidogenic APP processing and is, therefore, of potential therapeutic value.

Original languageEnglish (US)
Pages (from-to)1035-1040
Number of pages6
JournalNeuroreport
Volume10
Issue number5
DOIs
StatePublished - Apr 6 1999

Keywords

  • APP processing
  • Alzheimer's disease
  • Benzolactam
  • Fibroblasts
  • PC12
  • Protein kinase C
  • β- Amyloid

ASJC Scopus subject areas

  • Neuroscience(all)

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    Ibarreta, D., Duchén, M., Ma, D., Qiao, L., Kozikowski, A. P., & Etcheberrigaray, R. (1999). Benzolactam (BL) enhances sAPP secretion in fibroblasts and in PC12 cells. Neuroreport, 10(5), 1035-1040. https://doi.org/10.1097/00001756-199904060-00026