title: Evidence that the amyloid-β protein precursor intracellular domain, AICD, derives from β-secretase-generated C-terminal fragment.
abstract: One of the major pathological hallmarks of brains affected with Alzheimer's disease (AD) is the senile plaque, an extracellular deposit mainly composed of a set of highly insoluble peptides of various lengths (39-43 amino acids) referred to as amyloid-β (Aβ) peptides. Aβ peptides are derived from combined proteolytic cleavages undergone on the amyloid-β protein precursor (AβPP) by a set of enzymes called secretases. Several lines of anatomical and biological evidence suggest that Aβ peptides would not account for all pathological stigmata and molecular dysfunctions taking place in AD. In amyloidogenic and non-amyloidogenic pathways, AβPP first undergoes β- or α-secretases-mediated cleavages yielding C99 and C83, respectively. These two membrane-embedded C-terminal fragments are both potential targets of subsequent γ-secretase-mediated proteolysis. The latter cleavage not only generates either p3 or Aβ peptides but similarly gives rise to an AβPP IntraCellular Domain (AICD fragment) that could modulate the transcription of several genes linked to AD pathology. It is therefore striking that AICD theoretically derives from both amyloidogenic and non-amyloidogenic AβPP processing pathways. Here we show that AICD predominantly derives from C99 by means of recombinant substrates and transiently transfected cells expressing C99. Our data suggest a preferred pathogenic pathway for AICD production and suggests that this fragment, in addition to C99 and Aβ peptides, could contribute to AD pathology.
authors.affiliation: Université de Nice-Sophia-Antipolis, Institut de Pharmacologie Moléculaire et Cellulaire, UMR 6097 CNRS, Fondation pour la Recherche Médicale/Excellence Laboratory DISTALZ, Sophia-Antipolis, Valbonne, France.
authors.forename: Brice
authors.initials: B
authors.lastname: Flammang
authors.forename: Raphaëlle
authors.initials: R
authors.lastname: Pardossi-Piquard
authors.forename: Jean
authors.initials: J
authors.lastname: Sevalle
authors.forename: Delphine
authors.initials: D
authors.lastname: Debayle
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Dabert-Gay
authors.forename: Aurélie
authors.initials: A
authors.lastname: Thévenet
authors.forename: Inger
authors.initials: I
authors.lastname: Lauritzen
authors.forename: Frédéric
authors.initials: F
authors.lastname: Checler
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D047468:Immunoprecipitation; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism*; D009447:Neuroblastoma / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D059748:Proteolysis / Q000187:drug effects; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013379:Substrate Specificity / Q000187:drug effects; D013997:Time Factors; D014162:Transfection
chemical_list: D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D053829:Amyloid Precursor Protein Secretases