Effects of anoxia and hypoxia on amyloid precursor protein processing in cerebral microvascular smooth muscle cells.
Cerebral amyloid angiopathy (CAA) is characterized by the degeneration of cerebral microvascular smooth muscle cells (MV-SMC) and the replacement of normal vessel wall components by beta-amyloid (Abeta) protein. Little is known regarding the mechanisms of SMC degeneration in CAA. The effects of anoxia on the metabolism of the amyloid precursor protein (APP) were studied to investigate the MV-SMC response to anoxic stress and its possible role in the pathogenesis of CAA. MV-SMC exposed to chronic anoxia (24-48 hours) showed a decrease in expression of the 2 putative alpha-secretase enzymes, mature TACE (TNFalpha-converting enzyme) and ADAM10 (a disintegrin and metalloprotease). A concomitant decrease in the alpha-secretase cleavage products sAPPalpha and C83 was observed. Investigation of mRNA expression showed an increase in TACE and a sharp decrease in ADAM10 at 24 hours. Exposing MV-SMC to hypoxia (1% O2) revealed a different pattern of expression with no significant change in TACE protein, but an increase in TACE mRNA occurring at a later time point (48 hours). There was no change in ADAM10 mRNA expression, but a reduction in mature ADAM10 with a parallel increase in immature ADAM10 protein. These results demonstrate a requirement for oxygen in the regulation of the alpha-secretase pathway during APP metabolism.
Auerbach
Ilene D
ID
Department of Pathology and Laboratory Medicine (Neuropathology), the Brain Research Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Vinters
Harry V
HV
D051722:ADAM Proteins / Q000378:metabolism; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D015153:Blotting, Western / Q000379:methods; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D011466:Prostanoic Acids / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013997:Time Factors
C489697:APLP1 protein, human; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D011466:Prostanoic Acids; D012333:RNA, Messenger; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C035288:rosaprostol