Generation and regulation of β-amyloid peptide variants by neurons

Gunnar K. Gouras, Huaxi Xu, Jasmina N. Jovanovic, Joseph D. Buxbaum, Rong Wang, Paul Greengard, Norman R. Relkin, Sam Gandy

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107 Scopus citations


Studies of processing of the Alzheimer β-amyloid precursor protein (βAPP) have been performed to date mostly in continuous cell lines and indicate the existence of two principal metabolic pathways: the 'β- secretase' pathway, which generates β-amyloid (Aβ(1-40/42); ~4 kDa), and the 'α-secretase' pathway, which generates a smaller fragment, the 'p3' peptide (Aβ(17-40/42); ~3 kDa). To determine whether similar processing events underlie βAPP metabolism in neurons, media were examined following conditioning by primary neuronal cultures derived from embryonic day 17 rats. Immunoprecipitates of conditioned media derived from [35S]methionine pulse- labeled primary neuronal cultures contained 4- and 3-kDa Aβ-related species. Radiosequencing analysis revealed that the 4-kDa band corresponded to conventional Aβ beginning at position Aβ(Asp1), whereas both radio- sequencing and immunoprecipitation-mass spectrometry analyses indicated that the 3-kDa species in these conditioned media began with Aβ(Glu11) at the N terminus, rather than Aβ(Leu17) as does the conventional p3 peptide. Either activation of protein kinase C or inhibition of protein phosphatase 1/2A increased soluble βAPP(α) release and decreased generation of both the 4-kDa Aβ and the 3-kDa N-truncated Aβ. Unlike results obtained with continuously cultured cells, protein phosphatase 1/2A inhibitors were more potent at reducing Aβ secretion by neurons than were protein kinase C activators. These data indicate that rodent neurons generate abundant Aft variant peptides and emphasize the role of protein phosphatases in modulating neuronal Aβ generation.

Original languageEnglish
Pages (from-to)1920-1925
Number of pages6
JournalJournal of Neurochemistry
Issue number5
StatePublished - Nov 1998
Externally publishedYes


  • Alzheimer's disease
  • Amyloid precursor protein
  • Neurons
  • Protein kinase
  • Protein phosphatase
  • β-Amyloid peptides


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