Alternative, non-secretase processing of Alzheimer's beta-amyloid precursor protein during apoptosis by caspase-6 and-8

Citation
L. Pellegrini et al., Alternative, non-secretase processing of Alzheimer's beta-amyloid precursor protein during apoptosis by caspase-6 and-8, J BIOL CHEM, 274(30), 1999, pp. 21011-21016
Citations number
45
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
0021-9258 → ACNP
Volume
274
Issue
30
Year of publication
1999
Pages
21011 - 21016
Database
ISI
SICI code
0021-9258(19990723)274:30<21011:ANPOAB>2.0.ZU;2-I
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Altho ugh the pathogenesis of AD is unknown, it is widely accepted that AD is cau sed by extracellular accumulation of a neurotoxic peptide, known as A beta, Mutations in the beta-amyloid precursor protein (APP), from which A beta a rises by proteolysis, are associated with some forms of familial AD (FAD) a nd result in increased A beta production. Two other FAD genes, presenilin-1 and -2, have also been shown to regulate A beta production; however, studi es examining the biological role of these FAD genes suggest an alternative theory for the pathogenesis of AD. In fact, all three genes have been shown to regulate programmed cell death, hinting at the possibility that dysregu lation of apoptosis plays a primary role in causing neuronal loss in AD. In an attempt to reconcile these two hypotheses, we investigated APP processi ng during apoptosis and found that APP is processed by the cell death prote ases caspase-6 and -8. APP is cleaved by caspases in the intracellular port ion of the protein, in a site distinct from those processed by secretases. Moreover, it represents a general effect of apoptosis, because it occurs du ring cell death induced by several stimuli both in T cells and in neuronal cells.