Proteolytic imbalance in Alzheimer fibroblasts as potential pathological trait of disease

many Alzheimer researchers, consider that a single molecular trait could not be sufficient for biochemical AD diagnosis which, in turn, could be more reliably accomplished by complementation of distinct cellular markers. This assumption, however, implies the dysfunction of a rather `nonspecific' process, which might give rise to a variety of phenotypical and molecular effects as the results of metabolic amplification through side pathways. In our view, the abnormal control of proteolysis in AD cells might be the potentially unifying concept from which a panel of apparently unrelated alterations involving calcium regulation, oxidative metabolism, transduction system, and APP processing could be derived. Why resulting cellular and molecular derangements are mild in the majority of peripheral tissues including fibroblasts and so severe to the brain is still to be devised. We have, however, learned from cellular pathology that elementary lesions of cells potentially can produce numerous secondary biochemical alterations that might not be apparently related to the basic pathology of the disease. In addition, the functional and morphologic features of most affected tissues are not always readily pathognomonic of the disease and are sometimes anatomically distant. Knowing this, we see that cultured skin fibroblasts could be a useful model in seeking pathologic hallmarks of AD, but we must pay special attention to dysregulation of intracellular proteolysis as one of the possible pathogenetic mechanisms of the disease.