Alzheimer's Disease (AD), a neuropsychiatric disorder, is characterized by severe morbidity and is one of the leading causes of death in the elderly in the United States. It comprises more than 50% of the cases of dementia. Although considerable progress has been made in the genetics, neurochemical pathology, neuropsychology, and neuroanatomy of AD, little is available in the way of treatment, with the exception of the recent FDA approval of an acetylcholinesterase inhibitor, which is helpful only in a minority of patients. This revised competitive renewal application seeks to build upon our progress in characterizing the neurochemical pathology of neurons containing neuropeptides and other neurotransmitters in AD. The major focus of this application is intensive scrutiny of the nature of the pathological involvement of neurons containing corticotropin-releasing factor (CRF) in AD. Our group was the first to describe the marked reduction in CRF immunoreactivity in post-mortem brain tissue in patients with AD, and this finding has been widely confirmed. In the present application, we seek to scrutinize this finding more closely by measurement of several indices of CRF neuronal function in post-mortem brain tissue in AD and in controls. These measures include: CRF immunoreactivity, CRF receptor density and affinity, mRNA expression for both CRF and the CRF receptor, measurement of the concentration and expression of the newly discovered CRF binding protein, as well as measures of intracellular signal transduction in response to CRF. In addition, in view of the many reports of widespread serotonergic and noradrenergic neuronal dysfunction in AD, we shall utilize newly available antibodies to the 5-HT and NE transporters to determine the cellular localization and quantify the presynaptic 5-HT and NE transporter proteins in post-mortem brain samples. The resultant data will also provide novel information on the relationship between the pathological involvement of these three neurotransmitter systems in AD. Taken together, these experiments will further our understanding of the neurochemical pathology of AD and provide the basis for the development of novel therapies for this disorder.
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