The molecular substrates associated with neuronal aging and the death of massive numbers of subsets of neurons in idiopathic Parkinson's disease (PD) with and without dementia, and Alzheimer's disease (AD) with and without parkinsonism remain poorly characterized. Although the etiology of AD and PD may be multifactorial, and several pathways may lead to the selective, but massive loss of neurons in AD and PD, a detailed characterization of the molecular abnormalities that occur in association with the death of neurons represents important first steps in elucidating the mechanisms whereby neurons degenerate in these 2 distinct neurodegenerative conditions. This information also could provide a rational strategy for the discovery of clinical interventions as well as for the identification of early and specific markers of AD and PD. Accordingly, this Program Project will identify and characterize molecular disturbances in defined populations of central nervous system neurons (e.g. neurons in basal ganglia, brainstem, hippocampus, and olfactory epithelium) that degenerate in large numbers and thereby contribute to the extra- pyramidal deficits, memory loss and diminished olfaction observed in patients with PD and AD. To do this, a Clinical Core has been established to examine controls and patients with PD and/or AD bi-annually, and to develop """"""""step-down"""""""" procedures for monitoring patients with end stage disease. The tissues from subjects studies in the Clinical Core who come to autopsy will be assessed diagnostically by the Neuropathology Core which also will evaluate the potential specificity of novel olfactory epithelium lesions for AD, and distribute well characterized tissue samples to Project investigators. Using molecular probes (monoclonal antibodies, cDNAs) and postmortem tissues the following peptides and polypeptides will be examined in this Program Project: D1 and D2 dopamine receptors (Project 1); Senile plaque beta-amyloid peptides, their precursors and the tau and neurofilament components in plaque coronas (Project 2); Kinases that act on neuronal cytoskeletal proteins especially tau (Project 3). The peptides and proteins to be studied here have been clearly implicated in altered dopamine innervation, the formation of newly discovered neuritic in altered dopamine innervation, the formation of newly discovered neuritic pathology in Ad olfactory epithelium, and some of the hallmark lesions of PD and AD (e.g. senile plaques and other accumulations of amyloid and cytoskeletal protein fragments). Thus, this Program Project represents a comprehensive effort to characterize the molecular pathology of these lesions, and probe mechanisms whereby they arise and contribute to neuron death.
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