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-SMQ and the replacement of normal vessel wall components by beta-amyloid (A beta) 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 (2448 hours) showed a decrease in expression of the 2 putative alpha-secretase enzymes, mature TACE (TNF alpha-converting enzyme) and ADAM10 (a disintegrin and metalloprotease). A concomitant decrease in the a-secretase cleavage products sAPP alpha and C83 was observed. Investigation of mRNA expression showed an increase in TACE and a sharp decrease in ADAM 10 at 24 hours. Exposing MV-SMC to hypoxia (1% O-2) 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 ADAM 10 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 a-secretase pathway during APP metabolism.