title: Intracellular pH regulates amyloid precursor protein intracellular domain accumulation.
abstract: The amyloid precursor protein (APP) metabolism is central to pathogenesis of Alzheimer's disease (AD). Parenchymal amyloid deposits, a neuropathological hallmark of AD, are composed of amyloid-beta peptides (Abeta). Abeta derives from the amyloid precursor protein (APP) by sequential cleavages by beta- and gamma-secretases. Gamma-secretase cleavage releases the APP intracellular domain (AICD), suggested to mediate a nuclear signaling. Physiologically, AICD is seldom detected and thus supposed to be rapidly degraded. The mechanisms responsible of its degradation remain unknown. We used a pharmacological approach and showed that several alkalizing drugs induce the accumulation of AICD in neuroblastoma SY5Y cell lines stably expressing APP constructs. Moreover, alkalizing drugs induce AICD accumulation in naive SY5Y, HEK and COS cells. This accumulation is not mediated by the proteasome or metallopeptidases and is not the result of an increased gamma-secretase activity since the gamma-secretase cleavage of Notch1 and N-Cadherin is not affected by alkalizing drug treatments. Altogether, our data demonstrate for the first time that alkalizing drugs induce the accumulation of AICD, a mechanism likely mediated by the endosome/lysosome pathway.
authors.affiliation: INSERM U815, Centre Jean-Pierre Aubert, Neurodegenerative Disorders and Neuronal Death, 1, Place de Verdun, F-59045 Lille, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Vingtdeux
authors.forename: Malika
authors.initials: M
authors.lastname: Hamdane
authors.forename: Séverine
authors.initials: S
authors.lastname: Bégard
authors.forename: Anne
authors.initials: A
authors.lastname: Loyens
authors.forename: André
authors.initials: A
authors.lastname: Delacourte
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Beauvillain
authors.forename: Luc
authors.initials: L
authors.lastname: Buée
authors.forename: Philippe
authors.initials: P
authors.lastname: Marambaud
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sergeant
mesh_terms: D000468:Alkalies / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D007668:Kidney / Q000166:cytology; D008247:Lysosomes / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology; D009447:Neuroblastoma; D017434:Protein Structure, Tertiary; D051880:Receptors, Notch / Q000378:metabolism; D012995:Solubility; D014162:Transfection
chemical_list: D000468:Alkalies; D016564:Amyloid beta-Protein Precursor; D015820:Cadherins; D004791:Enzyme Inhibitors; D018942:Macrolides; D051880:Receptors, Notch; C057620:bafilomycin A; D053829:Amyloid Precursor Protein Secretases