Inflammatory, apoptotic, and survival gene signaling in Alzheimer's disease. A review on the bioactivity of neuroprotectin D1 and apoptosis.
Aging is associated with an enhanced susceptibility to brain dysfunction, loss of memory, and cognitive decline and significantly influences the quality of life for the affected individual. Recent molecular-genetic approaches have provided powerful insights into common age-related diseases that are both progressive and multifactorial, such as Alzheimer's disease (AD), and in vitro in AD models. These investigations have uncovered consistent deficits in brain gene signaling mechanisms and neurotrophic substances known to contribute to normal brain function. Inflammatory signaling pathways involving up-regulation of cytosolic phospholipase A(2) and the arachidonic acid cycle, the depletion of the brain-essential fatty acid docosahexaenoic acid (DHA) and DHA-derived neuroprotectin D1, and changes in the expression of key proapoptotic and antiapoptotic members of the Bcl-2 gene family are thought to be major contributors to pathogenic processes in degenerating brain tissue. This review will focus on the roles of stress genes, apoptosis-related genes, and inflammation in the molecular genetics of AD with emphasis on the interactive nature of inflammatory, neurotrophic, and apoptotic signaling and will highlight areas of rapid progress in the characterization of action of DHA and neuroprotectin D1 and address important research challenges. We also attempt to integrate these molecular, genetic, and neurochemical changes with cellular pathways involved in brain aging to formulate an integrated understanding of multifactorial age-related neurologic disease and pharmacotherapeutic strategies that may be useful in the restoration of homeostatic brain function.
Lukiw
Walter J
WJ
LSU Neuroscience Center of Excellence and Department of Ophthalmology, Louisiana State University Health Sciences Center, 2020 Gravier Street, Suite 904, New Orleans, LA 70112-2272, USA. wlukiw@lsuhsc.edu
Bazan
Nicolas G
NG
D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*
C487679:protectin D1; D004281:Docosahexaenoic Acids