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.