Hypoxia and neurodegeneration.
Periods of chronic hypoxia, which can arise from numerous cardiorespiratory disorders, predispose individuals to the development of dementias, particularly Alzheimer's disease (AD). AD is characterized in part by the increased production of amyloid beta peptide (Abeta), which forms the extracellular plaques by which the disease can be identified post mortem. Numerous studies have now shown that hypoxia, even in vitro, can increase production of Abeta in different cell types. Evidence has been produced to indicate hypoxia alters both expression of the Abeta precursor, APP, and also the expression of the secretase enzymes, which cleave Abeta from APP. Other studies implicate reduced Abeta degradation as a possible means by which hypoxia increases Abeta levels. Such variability may be attributable to cell-specific responses to hypoxia. Further evidence indicates that some, but not all of the cellular adaptations to chronic hypoxia (including alteration of Ca(2+) homeostasis) require Abeta formation. However, other aspects of hypoxic remodeling of cell function appear to occur independently of this process. The molecular and cellular responses to hypoxia contribute to our understanding of the clinical association of hypoxia and increased incidence of AD. However, it remains to be determined whether inhibition of one or more of the effects of hypoxia may be of benefit in arresting the development of this neurodegenerative disease.
Peers
Chris
C
Faculties of Medicine, University of Leeds, Leeds, United Kingdom. c.s.peers@leeds.ac.uk
Dallas
Mark L
ML
Boycott
Hannah E
HE
Scragg
Jason L
JL
Pearson
Hugh A
HA
Boyle
John P
JP
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D008954:Models, Biological; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology*
D016229:Amyloid beta-Peptides; D002118:Calcium