title: Amyloid peptides mediate hypoxic increase of L-type Ca2+ channels in central neurones.
abstract: Prolonged hypoxia, encountered in individuals suffering from various cardiorespiratory diseases, enhances the likelihood of subsequently developing Alzheimer's disease (AD). However, the underlying mechanisms are unknown, as are the mechanisms of neurodegeneration of amyloid beta peptides (AbetaPs), although the latter involves disruption of Ca2+ homeostasis. Here, immunohistochemistry demonstrated that hypoxia increased production of AbetaPs, an effect which was prevented by inhibition of either beta or gamma secretase, the enzymes required for liberation of AbetaP from its precursor protein. Whole-cell patch clamp recordings showed that hypoxia selectively increased functional expression of L-type Ca2+ channels. This was prevented by inhibition of either beta or gamma secretase, indicating that hypoxic channel up-regulation is dependent upon AbetaP formation. Our results indicate for the first time that hypoxia promotes AbetaP formation in central neurons, and show that this leads to abnormally high selective expression of L-type Ca2+ channels whose blockade has previously been shown to be neuroprotective in AD models. These findings provide a cellular basis for understanding the increased incidence of AD following prolonged hypoxia.
authors.affiliation: Institute for Cardiovascular Research, Schools of Medicine, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: N J
authors.initials: NJ
authors.lastname: Webster
authors.forename: M
authors.initials: M
authors.lastname: Ramsden
authors.forename: J P
authors.initials: JP
authors.lastname: Boyle
authors.forename: H A
authors.initials: HA
authors.lastname: Pearson
authors.forename: C
authors.initials: C
authors.lastname: Peers
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism*; D008564:Membrane Potentials / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D020746:Calcium Channels, L-Type; D010100:Oxygen