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Titolo:
Novel effects of FCCP [carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone] on amyloid precursor protein processing
Autore:
Connop, BP; Thies, RL; Beyreuther, K; Ida, N; Reiner, PB;
Indirizzi:
Univ British Columbia, Dept Psychiat, Kinsmen Lab Neurol Res, Vancouver, BC Univ British Columbia Vancouver BC Canada V6T 1Z3 urol Res, Vancouver, BC Univ British Columbia, Fac Pharmaceut Sci, Vancouver, BC V6T 1Z3, Canada Univ British Columbia Vancouver BC Canada V6T 1Z3 ver, BC V6T 1Z3, Canada Univ Heidelberg, Ctr Biol Mol, Heidelberg, Germany Univ Heidelberg Heidelberg Germany g, Ctr Biol Mol, Heidelberg, Germany
Titolo Testata:
JOURNAL OF NEUROCHEMISTRY
fascicolo: 4, volume: 72, anno: 1999,
pagine: 1457 - 1465
SICI:
0022-3042(199904)72:4<1457:NEOF[C>2.0.ZU;2-P
Fonte:
ISI
Lingua:
ENG
Soggetto:
ALZHEIMERS-DISEASE; BETA-PROTEIN; BAFILOMYCIN A1; PEPTIDE; CELLS; INHIBITOR; LYSOSOMES; PATHWAY; ATPASES; DOMAIN;
Keywords:
beta-amyloid precursor protein; beta-amyloid; carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone; acidic compartment; endosome; lysosome;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
47
Recensione:
Indirizzi per estratti:
Indirizzo: Reiner, PB UnivkBritish Columbia, Dept Psychiat, Kinsmen Lab Neurol Res, 2255 Westbroo Univ British Columbia 2255 Westbrook Mall Vancouver BC Canada V6T 1Z3
Citazione:
B.P. Connop et al., "Novel effects of FCCP [carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone] on amyloid precursor protein processing", J NEUROCHEM, 72(4), 1999, pp. 1457-1465

Abstract

Amyloidogenic processing of the beta-amyloid precursor protein (APP) has been implicated in the pathology of Alzheimer's disease. Because it has beensuggested that catabolic processing of the APP holoprotein occurs in acidic intracellular compartments, we studied the effects of the protonophore carbonyl cyanide rho-(trifluoromethoxy)phenylhydrazone (FCCP) and the ATPase inhibitor bafilomycin A1 on APP catabolism in human embryonic kidney 293 cells expressing either wild-type or "Swedish" mutant APP. Unlike bafilomycinA1, which inhibits beta-amyloid production in cells expressing mutant but not wild-type APP, FCCP inhibited beta-amyloid production in both cell types. Moreover, the effects of FCCP were independent of alterations in total cellular APP levels or APP maturation, and the concentrations used did not alter either cellular ATP levers or cell viability. Bafilomycin A1, which had no effect on beta-amyloid production in wird-type cells, inhibited endocytosis of fluorescent transferrin, whereas concentrations of FCCP that inhibited beta-amyloid production in these cells had no effect on endosomal function. Thus, in wild-type-expressing cells it appears that the beta-amyloid peptide is not produced in the classically defined endosome, Although bafilomycin A1 decreased beta-amyloid release from cells expressing mutant APP but not wild-type APP, it altered lysosomal function in both cell types, suggesting that in normal cells beta-amyloid is not produced in the lysosome. Although inhibition of beta-amyloid production by bafilomycin Al in mutant cells may occur via changes in endosomal/lysosomal pH, our data suggest that FCCP inhibits wild-type beta-amyloid production by acting on a bafilomycin A1-insensitive acidic compartment that is distinct from either the endosome or the lysosome.

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Documento generato il 02/04/20 alle ore 21:27:15