| This thesis focuses on the cell biology of Alzheimer's amyloid precursor protein (APP) and antigens associated with neurofibrillary tangles (NFT), namely tau, and antigens to Alz-50 and CD1. Tau, a microtubule associated protein, is a major known component of NFT, and Alz-50 and CD1 immunolabel NFT with high specificity. Ultrastructural studies showed that APP, (1) associated with cell surface microfibrils, which are involved in adhesive interactions of growth cones with their microenvironment, (2) occurred as microparticles on the substratum and, (3) incorporated into extracellular matrix. Correlating temporally with target innervation, APP down-regulated in chick retina, but in long term cultures it did not down-regulate, and instead accumulated in the extracellular space as microclusters, and as circular deposits of microparticles, which were similar to diffuse plaques of AD. Pattern of expression of APP in some neuroblastoma cell lines also suggested that APP is involved in cell-cell interactions. To understand the pathophysiology of NFT, expression of tau was compared to that of Alz-50 and CD1. In developing chick forebrain, the pattern of expression of CD1 antigen was remarkably similar to that of tau immunoreactivity. In chick retina, tau appeared in the first week of embryogenesis, and continued to be expressed in adult retina, whereas CD1, showing similar pattern of expression during early development, down regulated after conclusion of embryogenesis. In low density chick retina culture, tau appeared in all the processes, whereas in explants and high density cultures, tau was not present that extensively. Alz-50, was not expressed during development in vivo but appeared in dissociated chick retina culture. In B103 (rat neuroblastoma), and N1E (mouse neuroblastoma) cell lines, Alz-50 was present in every cell. Data suggest that (1) APP and CD1 antigen are expressed in embryo and undergo developmental down-regulation, and that they may be involved in neuritogenesis, (2) Inadequate cell-cell interactions may cause accumulation of amyloidogenic peptides in the extracellular space, and expression of tau in all the processes and cell body, and (3) Alz-50 is not a marker of cell death. It is speculated that NFT and senile plaques are end result of continuous abortive regeneration in the AD brain. |
