The long-term objective of this project is to evaluate the therapeutic potential of steroids for the treatment of Alzheimer's disease. The rationale for this approach lies in the notions that the brain synthesizes and accumulates specific steroids, that steroids induce choline acetyl transferase and acetylcholine esterase activities in cholinergic brain regions that undergo extensive degeneration during Alzheimer's disease, and that steroids in several systems promote neuronal survival and improve memory in aging laboratory animals. We will focus on olfactory regions of the brain which are earliest and most severely affected in Alzheimer's disease. Moreover, pathohistological changes in the olfactory epithelium of Alzheimer's patients have been reported. Since the olfactory epithelium is readily accessible and represents a homogeneous cell population with unusual plasticity, we will initially study the effects of steroids on cell survival in the olfactory neuroepithelium. We will initiate this project as a pilot study with the following goals: 1) To extend and consolidate previous observations that histological changes diagnostic of Alzheimer's disease occur in the olfactory epithelium itself, using intracellular injections of Lucifer Yellow in lightly fixed human tissue from rapid autopsies, followed by observation under a confocal microscope and three- dimensional reconstruction of individual olfactory neurons; and, 2) To measure tissue levels of two representative steroids, pregnenolone and dehydroepiandrosterone, in olfactory regions of human brain obtained by rapid autopsy. These studies will provide a detailed documentation of histopathological alterations that occur in the olfactory epithelium of Alzheimer's patients as compared to age-matched controls and will indicate whether there are in Alzheimer's patients statistically significant alterations in endogenous levels of steroids in different brain regions. Information from these pilot studies will provide a solid experimental basis for an extended research program.
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