PRESERVATION OF NATIVE CONFORMATION DURING ALUMINUM-INDUCED AGGREGATION OF TAU-PROTEIN

ALUMINIUM exposure has been shown to result in aggregation of microtub ule-associated protein tau in vitro. In the light of recent observatio ns that the native random structure of tau protein is maintained in it s monomeric and dimeric states as well as in the paired helical filame nts characteristic of Alzheimer's disease, it is likely that factors p laying a causative role in neurofibrillary pathology would not drastic ally alter the native conformation of tau protein. We have studied the interaction of tau protein with aluminium using circular dichroism (C D) and 27(Al) NMR spectroscopy. The CD studies revealed a five-fold in crease in the observed ellipticity of the tau-aluminium assembly. The increase in elipticity was not associated with a change in the general conformation of the protein and was most likely due to an aggregation of the tau protein induced by aluminium. Al-27 NMR spectroscopy confi rmed the binding of aluminium to tau protein. Hyperphosphorylation of tau in Alzheimer's disease is known to be associated with defective mi crotubule assembly in this condition. Abnormally phosphorylated tau ex ists in a polymerized form in the paired helical filaments (PHF) which constitute the neurofibrillary tangles found in Alzheimer's disease. While it is hypothesized that its altered biophysical characteristics render abnormally phosphorylated tau resistant to proteolysis, causing the formation of stable deposits,the sequence of events resulting in the polymerization of tau are little understood, as are the additional factors or modifications required for tills process. Based on the res ults of our spectroscopic studies, a model for the sequence of events occurring in neurofibrillary pathology is proposed.