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Elevation of beta-amyloid peptide 2-42 in sporadic and familial Alzheimer's disease and its generation in PS1 knockout cells.

Abstract
Urea-based beta-amyloid (Abeta) SDS-polyacrylamide gel electrophoresis and immunoblots were used to analyze the generation of Abeta peptides in conditioned medium from primary mouse neurons and a neuroglioma cell line, as well as in human cerebrospinal fluid. A comparable and highly conserved pattern of Abeta peptides, namely, 1-40/42 and carboxyl-terminal-truncated 1-37, 1-38, and 1-39, was found. Besides Abeta1-42, we also observed a consistent elevation of amino-terminal-truncated Abeta2-42 in a detergent-soluble pool in brains of subjects with Alzheimer's disease. Abeta2-42 was also specifically elevated in cerebrospinal fluid samples of Alzheimer's disease patients. To decipher the contribution of potential different gamma-secretases (presenilins (PSs)) in generating the amino-terminal- and carboxyl-terminal-truncated Abeta peptides, we overexpressed beta-amyloid precursor protein (APP)-trafficking mutants in PS1+/+ and PS1-/- neurons. As compared with APP-WT (primary neurons from control or PS1-deficient mice infected with Semliki Forest virus), PS1-/- neurons and PS1+/+ neurons overexpressing APP-Deltact (a slow-internalizing mutant) show a decrease of all secreted Abeta peptide species, as expected, because this mutant is processed mainly by alpha-secretase. This drop is even more pronounced for the APP-KK construct (APP mutant carrying an endoplasmic reticulum retention motif). Surprisingly, Abeta2-42 is significantly less affected in PS1-/- neurons and in neurons transfected with the endocytosis-deficient APP-Deltact construct. Our data confirm that PS1 is closely involved in the production of Abeta1-40/42 and the carboxyl-terminal-truncated Abeta1-37, Abeta1-38, and Abeta1-39, but the amino-terminal-truncated and carboxyl-terminal-elongated Abeta2-42 seems to be less affected by PS1 deficiency. Moreover, our results indicate that the latter Abeta peptide species could be generated by a beta(Asp/Ala)-secretase activity.
AuthorsJ Wiltfang, H Esselmann, P Cupers, M Neumann, H Kretzschmar, M Beyermann, D Schleuder, H Jahn, E Rüther, J Kornhuber, W Annaert, B De Strooper, P Saftig
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 276 Issue 46 Pg. 42645-57 (Nov 16 2001) ISSN: 0021-9258 [Print] United States
PMID11526104 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Amyloid beta-Peptides
  • DNA, Complementary
  • Peptide Fragments
  • Peptides
  • amyloid beta-protein (1-42)
  • amyloid beta-protein (2-42)
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • Bace1 protein, mouse
Topics
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease (cerebrospinal fluid, metabolism)
  • Amino Acid Sequence
  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Peptides (biosynthesis, cerebrospinal fluid, chemistry)
  • Animals
  • Aspartic Acid Endopeptidases (metabolism)
  • Brain (metabolism)
  • Cell Line
  • Cells, Cultured
  • DNA, Complementary (metabolism)
  • Electrophoresis, Gel, Two-Dimensional
  • Electrophoresis, Polyacrylamide Gel
  • Endopeptidases
  • Endoplasmic Reticulum (metabolism)
  • Humans
  • Immunoblotting
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Molecular Sequence Data
  • Mutation
  • Neurons (metabolism)
  • Peptide Fragments (biosynthesis, cerebrospinal fluid, chemistry)
  • Peptides (chemistry)
  • Precipitin Tests
  • Protein Binding
  • Protein Structure, Tertiary
  • Semliki forest virus (genetics)
  • Sequence Homology, Amino Acid
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

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