Various respiratory and cardiovascular diseases leave individuals hypoxic for prolonged periods. For the central nervous system, the most extreme O₂ deprivation follows a stroke, but other diseases also compromise its O₂ supply. Prolonged hypoxia predisposes individuals to developing dementias, primarily Alzheimer's disease (AD). We have found that hypoxia (2.5 – 1% O₂, 6-48 h) alters aspects of neuronal and astrocytic function, and these are associated with production of amyloid b peptide (Ab), the main pathogenic factor in AD. In neurones, hypoxia selectively up-regulated L-type Ca²⁺ channels; this was prevented by inhibition of secretases required for Ab formation (Webster et al. 2006). Parallel studies employing recombinant channels indicated that Ab acted post-transcriptionally to alter Ca²⁺ channel trafficking such that more channels were present in the plasma membrane (Scragg et al. 2005). In astrocytes, hypoxia altered Ca²⁺ signalling via disruption of mitochondrial Ca²⁺ buffering and inhibition of Na⁺/Ca²⁺ exchange (Smith et al. 2003; Atkinson et al. 2006), effects which were also associated with Ab formation (Smith et al. 2004). Thus, Ab formation is linked with hypoxic remodelling of cell functions, any of which can contribute to disruption of Ca²⁺ homeostasis and so to neurodegeneration of AD. We are currently investigating the mechanisms by which production and degradation of Ab is modified by hypoxia.

Supported by The Alzheimer's Research Trust and MRC

Atkinson L., et al (2006) Neuroreport 17, 649-652; Scragg J. L., et al (2005) FASEB J. 19, 150-152; Smith I. F., et al (2004) J. Neurochem. 88, 869-877; Smith I. F., et al (2003) J. Biol. Chem. 278, 4875-4881; Webster N. J. et al (2006) Neurobiol. Aging 27, 439-445.