Intracellular Abeta and C99 aggregates induce mitochondria-dependent cell death in human neuroglioma H4 cells through recruitment of the 20S proteasome subunits.
Recent studies have reported that neuronal apoptosis is induced not only by extracellular Abeta but also by intracellular Abeta; however, the mechanism by which intracellular Abeta contributes to the regulation of cell death associated with the pathogenesis of AD remains to be elucidated. Using immunological assays and a short-lived enhanced green fluorescent protein (d2EGFP) system, we showed that intracellular Abeta and C99 form perinuclear aggregates in the cytosol, and the resulting aggregates attenuate the activity of the 26S proteasome. In addition, the immunofluorescence assays (IFA) revealed that the 20S proteasome alpha-subunits are recruited into perinuclear aggregates in both human embryonic kidney (HEK293) and human neuroglioma H4 (H4) cells. Interestingly, we observed an increase in the levels of Bax, cleavage of PARP-1, and mitochondrial release of proapoptotic proteins, such as cytochrome c and HtrA2, in H4 cells with intracellular Abeta or C99 aggregates, but not in HEK293 cells with those aggregates. The results of the present study indicate that intracellular Abeta and C99 aggregates induce mitochondria-dependent apoptotic cell death via elevation of Bax levels as a result of proteasome inhibition in a cell type-specific manner.
School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
Hyo-Jin
HJ
Park
Sang-Soo
SS
Kim
Seongman
S
Kang
Hyangshuk
H
Rhim
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D003600:Cytosol / Q000378:metabolism / Q000473:pathology; D004734:Energy Metabolism / Q000502:physiology; D005455:Fluorescent Antibody Technique; D005910:Glioma; D049452:Green Fluorescent Proteins; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology; D010446:Peptide Fragments / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D054875:Ubiquitination; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D051017:Apoptosis Regulatory Proteins; D010446:Peptide Fragments; D051028:bcl-2-Associated X Protein; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D046988:Proteasome Endopeptidase Complex