Neuritic plaques are composed of dystrophic neurites, amyloid fibrils, and astrocytic processes. We have previously observed that in the molecular layer of the dentate gyrus, the plaques ate localized along the middle of the molecular layer. This zone is differentiate by the loss of entorhirnal neurons in AD and we have proposed that the plaques in this region on result from an aberrants prolong response. In this propose, we argue that mechanisms associates with sprouting contribute to not only the neuritic elements within plaques, but may also account for the goal process and amyloid fibrils. An animal model system for the investigation of sprouting mechanisms has been the molecular layer of the dentate gyrus, due to its laminar organization and well characterized afferent and efferent connections. In AD, this region contains a high density of neuritic plaques. The molecular layer of the dentate gyrus is thus an excellent model system in which to examine neuritic plaque formation. The experiments outlined in this proposal will utilize the molecular layer of the dentate gyrus to investigate the contribution of sprouting to the neuritic, glial, and amyloid components of neuritic plaques. We will determine the relationship between plaques in this region and tangles in the major afferent inputs. We will determine if the plaque is associated with a vascular component. We will compare the glial response in AD to that observed in animal lesion models and compare the transmitter composition of plaques to that observed in the sprouting fibers. The key experiments will examine whether or not the gene for amyloid-B-proteins is induced during sprouting. In summary, the experiments are designed to demonstrate that plaques result from an aberrant or exaggerated response to neuronal loss and denervation.
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