| One of the histological findings necessary for making a diagnosis of Alzheimer's disease is the cytoskeletal pathology termed the neurofibrillary tangle. Tangles are a somatodendritic protein aggregation made up, almost entirely, of hyperphosphorylated forms of the microtubule associated protein, tau. These phosphorylations have been termed "aberrant" due to their ability for decreasing tau's microtubule stabilizing function.; We have developed a culture system of embryonic rat hippocampal neurons for studying developmentally occurring Alzheimer's disease-associated tau phosphorylations. Temporally unique phosphorylations of two of the Alzheimer's sites were observed during neuronal differentiation using the phosphoepitope, anti-tau antibodies, PHF-1 and Tau 1. Neurons were examined at various stages of differentiation by immunohistochemistry and western blotting. PHF-1 immunoreactive tau was bound specifically to axonal microtubules at all times while Tau 1 immunoreactive tau was never observed to bind microtubules. We determined that protein kinase C activity was required for the maintenance of phosphorylation of both epitopes.; Results from this study support the theory that increased phosphorylation of tau in Alzheimer's disease is an indication of attempted neuron growth or regeneration. In fact, PHF-1 immunoreactive tau was specifically bound to microtubules of growing axons. We suggest that tau phosphorylation is not pathological, per se, but is a response to some undetermined stimuli. By identifying kinase activities required for these specific phosphorylations, therapeutic strategies for augmenting or inhibiting them can be developed.; We found further evidence that tau phosphorylations are associated with growth using the phosphoepitope, monoclonal antibody, MPM 2. We identified a mitosis-associated phosphorylation of tau protein that was increased in AD brains compared to controls on western blots. Immunocytochemically, tau phosphorylated at this epitope was found within tangles.; Our final results are from an immunocytochemical study performed on the medulla of Alzheimer's disease brains. As far as we know, this is the first report of Alzheimer's-type tau pathology in the reticular formation. The tangles identified in this region were recognized with select anti-tau antibodies suggesting that they are unique from neocortical tangles. |
