Intracellular pH regulates amyloid precursor protein intracellular domain accumulation.
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.
Vingtdeux
Valérie
V
INSERM U815, Centre Jean-Pierre Aubert, Neurodegenerative Disorders and Neuronal Death, 1, Place de Verdun, F-59045 Lille, France.
Hamdane
Malika
M
Bégard
Séverine
S
Loyens
Anne
A
Delacourte
André
A
Beauvillain
Jean-Claude
JC
Buée
Luc
L
Marambaud
Philippe
P
Sergeant
Nicolas
N
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
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