Caspase cleaved presenilin-1 is part of active gamma-secretase complexes
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Caspase cleaved presenilin-1 is part of active gamma-secretase complexes. / Hansson, Camilla A; Popescu, Bogdan O; Laudon, Hanna; Cedazo-Minguez, Angel; Popescu, Laurentiu M; Winblad, Bengt; Ankarcrona, Maria; Petersen, Anna Camilla Hansson.
In: Journal of Neurochemistry, Vol. 97, No. 2, 2006, p. 356-64.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Caspase cleaved presenilin-1 is part of active gamma-secretase complexes
AU - Hansson, Camilla A
AU - Popescu, Bogdan O
AU - Laudon, Hanna
AU - Cedazo-Minguez, Angel
AU - Popescu, Laurentiu M
AU - Winblad, Bengt
AU - Ankarcrona, Maria
AU - Petersen, Anna Camilla Hansson
PY - 2006
Y1 - 2006
N2 - gamma-Secretase is a key enzyme involved in the processing of the beta-amyloid precursor protein into amyloid beta-peptides (Abeta). Abeta accumulates and forms plaques in Alzheimer's disease (AD) brains. A progressive neurodegeneration and cognitive decline occurs during the course of the disease, and Abeta 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 gamma-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 gamma-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 gamma-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 gamma-secretase complex in SH-SY5Y cells exposed to STS. In addition, Abeta was detected in medium from apoptotic HEK APP(swe) cells. Together, the data show that gamma-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.
AB - gamma-Secretase is a key enzyme involved in the processing of the beta-amyloid precursor protein into amyloid beta-peptides (Abeta). Abeta accumulates and forms plaques in Alzheimer's disease (AD) brains. A progressive neurodegeneration and cognitive decline occurs during the course of the disease, and Abeta 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 gamma-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 gamma-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 gamma-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 gamma-secretase complex in SH-SY5Y cells exposed to STS. In addition, Abeta was detected in medium from apoptotic HEK APP(swe) cells. Together, the data show that gamma-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.
KW - Amyloid Precursor Protein Secretases
KW - Amyloid beta-Protein Precursor
KW - Apoptosis
KW - Aspartic Acid Endopeptidases
KW - Blotting, Western
KW - Caspases
KW - Cell Line, Tumor
KW - Cell Survival
KW - Chromatin
KW - Endopeptidases
KW - Enzyme Activation
KW - Enzyme Inhibitors
KW - Humans
KW - Immunoprecipitation
KW - Luciferases
KW - Membrane Proteins
KW - Multiprotein Complexes
KW - Mutation
KW - Neuroblastoma
KW - Peptide Fragments
KW - Presenilin-1
KW - Protein Structure, Tertiary
KW - Staurosporine
KW - Subcellular Fractions
KW - Tetrazolium Salts
KW - Thiazoles
KW - Transfection
U2 - 10.1111/j.1471-4159.2006.03735.x
DO - 10.1111/j.1471-4159.2006.03735.x
M3 - Journal article
C2 - 16539675
VL - 97
SP - 356
EP - 364
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
SN - 0022-3042
IS - 2
ER -
ID: 41992240