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Caspase cleaved presenilin‐1 is part of active γ‐secretase complexes
Author(s) -
Hansson Camilla A.,
Popescu Bogdan O.,
Laudon Hanna,
CedazoMinguez Angel,
Popescu Laurentiu M.,
Winblad Bengt,
Ankarcrona Maria
Publication year - 2006
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2006.03735.x
Subject(s) - presenilin , nicastrin , amyloid precursor protein , neurodegeneration , staurosporine , gamma secretase , microbiology and biotechnology , caspase , chemistry , apoptosis , alpha secretase , amyloid precursor protein secretase , biology , alzheimer's disease , biochemistry , programmed cell death , signal transduction , medicine , disease , protein kinase c
γ‐Secretase is a key enzyme involved in the processing of the β‐amyloid precursor protein into amyloid β‐peptides (Aβ). Aβ accumulates and forms plaques in Alzheimer's disease (AD) brains. A progressive neurodegeneration and cognitive decline occurs during the course of the disease, and Aβ is believed to be central for the molecular pathogenesis of AD. Apoptosis has been implicated as one of the mechanisms behind the neuronal cell loss seen in AD. We have studied preservation and activity of the γ‐secretase complex during apoptosis in neuroblastoma cells (SH‐SY5Y) exposed to staurosporine (STS). We report that the known components (presenilin, Nicastrin, Aph‐1 and Pen‐2) interact and form active γ‐secretase complexes in apoptotic cells. In addition, the fragments corresponding to the PS1 N‐terminal fragment and the caspase‐cleaved PS1 C‐terminal fragment (PS1‐caspCTF) were found to form active γ‐secretase complexes when co‐expressed in presenilin (PS) knockout cells. Interestingly, PS1‐caspCTF replaced the normal PS1 C‐terminal fragment and was co‐immunoprecipitated with the γ‐secretase complex in SH‐SY5Y cells exposed to STS. In addition, Aβ was detected in medium from apoptotic HEK APP swe cells. Together, the data show that γ‐secretase complexes containing PS1‐caspCTF are active, and suggest that this proteolytic activity is also important in dying cells and may affect the progression of AD.