Molecular Gerontology of the Human Olfactory System

The human olfactory mucosa, olfactorybulb,and anterior olfactorynucleusexhibitcellular,molecular,and functional changes as a correlate of aging and of Alzheimer's disease. Among these changes are both peripheral and central neurodegeneration. The long term objectives of this research are to gain insight into the cellular and molecular mechanisms that induce neurodegeneration in the neurons of the olfactory epithelium, olfactory bulb, and anterior olfactory nucleus as humans age and as a consequence of Alzheimer's disease, and to identity measures of cellular and molecular olfactory neuropathology related to Alzheimer's disease that may correlate with central neuropathological criteria and clinical tests of dementia. The specific aims of this proposal are to investigate the impact of oxidative stress on olfactory neurons during the course of healthy aging and in patients with Alzheimer's disease by investigating antioxidant enzyme levels, molecular indicators of oxidative damage, and apoptotic neuronal death. These studies will utilize human postmortem olfactory tissues ITomclinically wellcharacterized non-demented elderly subjects and ITompatients with Alzheimer's disease recruited by the NllIINIA-funded Alzheimer's Disease Research Center at the Sanders-Brown Center on Aging. Tissues will be probed with immunohistochemical and molecular reagents that are indicative of exposure to sources of oxidative stress and of apoptotic cell death in order to identify and characterize age- and Alzheimer's disease-related changes among the young-old, old-old, and oldest-old, and in age-matched patients with Alzheimer's disease. Immunohistochemistry will be used to localize cellular changes, and quantitative biochemical/molecular analyses and stereo logical techniques will be used to assess their severity and to compare between groups. With the numbers of the oldest-old growing more rapidly than other segment of the population, and with age being a major risk factor for Alzheimer's disease, insight into neurodegenerative mechanisms that contribute to olfactory dysfunction may be of translational and therapeutic value in future patient-oriented research.