Generation and regulation of β-amyloid peptide variants by neurons

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Abstract

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.

Detaljer

Författare
  • Gunnar K. Gouras
  • Huaxi Xu
  • Jasmina N. Jovanovic
  • Joseph D. Buxbaum
  • Rong Wang
  • Paul Greengard
  • Norman R. Relkin
  • Sam Gandy
Externa organisationer
  • Weill Cornell Medical College
  • Rockefeller University
  • New York University
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Neurovetenskaper

Nyckelord

Originalspråkengelska
Sidor (från-till)1920-1925
TidskriftJournal of Neurochemistry
Volym71
Utgåva nummer5
StatusPublished - 1998 nov 1
PublikationskategoriForskning
Peer review utfördJa
Externt publiceradJa