Hypoxia signaling to genes: significance in Alzheimer's disease.
Aberrations in neural signaling, converging to and diverging from oxidative metabolism and blood supply, contribute to the initiation and maintenance of inflammatory responses, neuronal degeneration, and age-related cognitive decline in Alzheimer's disease (AD). Hypoxia/ischemia triggers phospholipase A2, leading to the accumulation of free arachidonic and docosahexaenoic acids (AA, DHA), as well as that of lysophospholipids. Some of these bioactive lipid messengers in turn give rise to several downstream lipid messengers, such as platelet-activating factor (PAF) and ecosanoids (prostaglandins and leukotrienes). Eicosanoid synthesis is highly regulated in hypoxia and in reperfusion subsequent to ischemia. As one of the consequences, mitochondrial function is disrupted and reactive oxygen species (ROS) both contribute to the expansion of cellular inflammatory responses and reduce the expression of genes required to maintain synaptic structure and function. On the other hand, pro-inflammatory genes are up-regulated. One of these, the inducible cyclooxygenase-2 (COX-2), along with oxygen-starved mitochondria, comprise the major sources of ROS in the brain during hypoxia, ischemia, and reperfusion. One outcome is a sustained metabolic stress that drives progressive dysfunction, apoptosis and/or necrosis, and brain cell death. How hypoxia modulates oxygen-sensitive gene expression is not well understood. Pro-inflammatory gene families that contribute to neurodegeneration are transiently activated in part by the heterodimeric oxygen-sensitive DNA-binding proteins nuclear factor for kappa B (NF-kappaB) and hypoxia-inducible factor-alpha (HIF-1alpha). Here the authors summarize current studies supporting the hypothesis that synaptically-derived lipid messengers play significant roles in ischemic stroke and that hypoxia is an important contributor to the onset and progression of AD neurodegeneration.
Bazan
Nicolas G
NG
Neuroscience Center and Department of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans 70112-2272, USA.
Palacios-Pelaez
Ricardo
R
Lukiw
Walter J
WJ
D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism; D006801:Humans; D002534:Hypoxia, Brain / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*