Neuritic plaques are a key feature of Alzheimer's disease and normal aging. Neuritic plaques within the hippocampal formation have a very characteristic distribution in the molecular layer of the fascia dentata, where they are aligned parallel to the granule cell layer. This precise, predictable pattern provides a unique opportunity to define plaque localization in terms of both the distribution of afferents to the molecular layer and the morphology granule cell dendrites. Two sets of experiments will test the hypothesis that changes in the distribution of afferents and changes in the morphology of granule cells develop as the first plaques appear. The third set of experiments will examine the role of microglia and amyloid in plaque formation in this well-defined population of neuritic plaques. The ultimate goal of these experiments is to develop the molecular layer of the fascia dentata as a model system in which to examine the pathogenesis of neuritic plaques in Alzheimer's disease. First, the distribution of afferents to the molecular layer in control and Alzheimer's disease patients will be related to the laminar distribution of neuritic plaques. Multiple anatomic markers will be used in each Rapid Autopsy case. The perforant path from the entorhinal cortex will be labeled with the fluorescent dye Dil. The cholinergic afferents from the basal forebrain cholinergic nuclei will be labeled with acetylcholinesterase histochemistry. Somatostatin and cholecystokinin afferents will be labeled immunohistochemically. Second, the relationships between the neuritic plaques and the granule cells will be defined. Intracellular injections of Lucifer yellow will fill the dendritic trees so that dendritic branching patterns and dendritic pathology can be correlated with plaque location. The distribution of abnormal granule cell bodies containing neurofibrillary tangles, Pick-like bodies, or abnormal neurofilament antigens will be correlated with the distribution of plaques in the overlying molecular layer. Third, patterns of accumulation of microglia and amyloid will be related to the above changes in the neuropil, using RCA-1 lectin histochemistry to label microglia and Congo red staining and amyloid beta protein immunochemistry to label amyloid. Amyloid deposition will also be correlated with the age of onset of dementia, duration of dementia, and family history of dementia.
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