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

Luca Pellegrini, Brent J. Passer, Massimo Tabaton, J. Kelly Ganjei, Luciano D'Adamio

Research output: Contribution to journalArticle

126 Citations (Scopus)

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Although the pathogenesis of AD is unknown, it is widely accepted that AD is caused by extracellular accumulation of a neurotoxic peptide, known as Aβ. Mutations in the β-amyloid precursor protein (APP), from which Aβ arises by proteolysis, are associated with some forms of familial AD (FAD) and result in increased Aβ production. Two other FAD genes, presenilin-1 and -2, have also been shown to regulate Aβ production; however, studies 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 dysregulation of apoptosis plays a primary role in causing neuronal loss in AD. In an attempt to reconcile these two hypotheses, we investigated APP processing during apoptosis and found that APP is processed by the cell death proteases caspase-6 and -8. APP is cleaved by caspases in the intracellular portion of the protein, in a site distinct from those processed by secretases. Moreover, it represents a general effect of apoptosis, because it occurs during cell death induced by several stimuli both in T cells and in neuronal cells.

Original languageEnglish (US)
Pages (from-to)21011-21016
Number of pages6
JournalJournal of Biological Chemistry
Volume274
Issue number30
DOIs
StatePublished - Jul 23 1999
Externally publishedYes

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Caspase 6
Caspase 8
Amyloid beta-Protein Precursor
Alzheimer Disease
Apoptosis
Cell death
Processing
Cell Death
Genes
Presenilin-2
Proteolysis
Presenilin-1
Amyloid Precursor Protein Secretases
T-cells
Caspases
Neurodegenerative Diseases
Peptide Hydrolases
T-Lymphocytes
Peptides
Mutation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Alternative, non-secretase processing of Alzheimer's β-amyloid precursor protein during apoptosis by caspase-6 and -8. / Pellegrini, Luca; Passer, Brent J.; Tabaton, Massimo; Ganjei, J. Kelly; D'Adamio, Luciano.

In: Journal of Biological Chemistry, Vol. 274, No. 30, 23.07.1999, p. 21011-21016.

Research output: Contribution to journalArticle

Pellegrini, Luca ; Passer, Brent J. ; Tabaton, Massimo ; Ganjei, J. Kelly ; D'Adamio, Luciano. / Alternative, non-secretase processing of Alzheimer's β-amyloid precursor protein during apoptosis by caspase-6 and -8. In: Journal of Biological Chemistry. 1999 ; Vol. 274, No. 30. pp. 21011-21016.
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