Abstract
Apoptotic cell death and increased production of amyloid b peptide (Ab) are pathological features of Alzheimer's disease (AD), although the exact contribution of apoptosis to the pathogenesis of the disease remains unclear. Here we describe a novel pro-apoptotic function of calsenilin/DREAM/KChIP3. By antisense oligonucleotide-induced inhibition of calsenilin/DREAM/KChIP3 synthesis, apoptosis induced by Fas, Ca2+-ionophore, or thapsigargin is attenuated. Conversely, calsenilin/DREAM/KChIP3 expression induced the morphological and biochemical features of apoptosis, including cell shrinkage, DNA laddering, and caspase activation. Calsenilin/DREAM/KChIP3-induced apoptosis was suppressed by caspase inhibitor Z-VAD and by Bcl-XL, and was potentiated by increasing cytosolic Ca2+, expression of Swedish amyloid precursor protein mutant (APPSW) or presenilin 2 (PS2), but not by a PS2 deletion lacking its C-terminus (PS2/411stop). In addition, calsenilin/DREAM/KChIP3 expression increased Ab42 production in cells expressing APPsw, which was potentiated by PS2, but not by PS2/411stop, which suggests a role for apoptosis-associated Ab42 production of calsenilin/DREAM/KChIP3.
MeSH terms
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Amino Acid Chloromethyl Ketones / pharmacology
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Amyloid beta-Peptides / genetics
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Amyloid beta-Peptides / metabolism
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Animals
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Apoptosis*
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Blotting, Western
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Calcium / metabolism*
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / metabolism*
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Cells, Cultured
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Cysteine Proteinase Inhibitors / pharmacology
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Humans
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Jurkat Cells
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Kv Channel-Interacting Proteins
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Neuroblastoma
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Oligonucleotides, Antisense / metabolism*
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Peptide Fragments / genetics
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Peptide Fragments / metabolism
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Presenilin-2
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Rats
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Transfection
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bcl-X Protein
Substances
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Amino Acid Chloromethyl Ketones
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Amyloid beta-Peptides
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BCL2L1 protein, human
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Bcl2l1 protein, rat
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Calcium-Binding Proteins
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Cysteine Proteinase Inhibitors
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KCNIP3 protein, human
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Kcnip3 protein, rat
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Kv Channel-Interacting Proteins
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Membrane Proteins
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Oligonucleotides, Antisense
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PSEN2 protein, human
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Peptide Fragments
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Presenilin-2
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Proto-Oncogene Proteins c-bcl-2
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Repressor Proteins
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amyloid beta-protein (1-42)
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bcl-X Protein
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benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
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Calcium