Hypoxia and Alzheimer's disease.
Numerous cardiorespiratory disorders result in persistent systemic hypoxia, or at worst (as a consequence of stroke) deprive the brain of oxygen completely for a period of time. Patients suffering from such conditions are much more susceptible to the development of dementias such as AD (Alzheimer's disease). Until recently, the cellular and molecular basis for the predisposition to AD by systemic hypoxia has been completely unknown. However, emerging evidence suggests that pathological cellular remodelling caused by chronic hypoxia shows striking similarities to those observed in the central nervous system as a consequence of AD. Furthermore, prolonged hypoxia can induce formation of Abetas (amyloid beta peptides), the primary neurotoxic elements of AD, which accumulate over years to form the extracellular plaques that are the hallmark feature of the disease. Hypoxia can lead to paradoxical increases in mitochondrial ROS (reactive oxygen species) generation upstream of Abeta formation. The downstream consequences of prolonged hypoxia include remodelling of functional expression of voltage-gated calcium channels and disturbance of intracellular calcium homoeostasis via disrupted calcium buffering and inhibition of calcium extrusion mechanisms. These effects can be mimicked by application of exogenous Abeta and, crucially, appear to depend on Abeta formation. Current knowledge supports the concept that prevention of the deleterious effects of hypoxia may prove beneficial in slowing or preventing the onset of AD.
Peers
Chris
C
Faculty of Medicine, University of Leeds, Leeds LS2 9JT, UK. c.s.peers@leeds.ac.uk
Pearson
Hugh A
HA
Boyle
John P
JP
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D001921:Brain / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D006801:Humans; D000860:Hypoxia; D002534:Hypoxia, Brain; D008954:Models, Biological; D009410:Nerve Degeneration; D010100:Oxygen; D010766:Phosphorylation; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D013997:Time Factors
D015220:Calcium Channels; D017382:Reactive Oxygen Species; D010100:Oxygen; D002118:Calcium