AGING AND ALZHEIMER DEMENTIA: ROLE OF FIBROUS PROTEIN

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This project is aimed at understanding the biochemistry, biology and molecular pathogenesis of Alzheimer's disease and senile dementia of the Alzheimer type (SDAT), the two most common neurological disorders accompanying aging. In these disorders, the main histopathological lesion is the presence of neurofibrillary tangles in the cerebral cortex. We have recently developed a method to purify SDAT tangles to a high degree from autopsied brains. We plan to characterize the purified tangles biochemically, and compare their amino acid compositions, peptide maps and amino acid sequences to that of intermediate filament proteins. We will focus on two classes of intermediate filament proteins, neurofilament triplet proteins and vimentin, which share immunological properties with neurifibrillary tangles. We will determine whether cross-links of di-, tri-tyrosine or Epsilon (Gamma-glutamyl) lysine are present in the tangle proteins, and finally we will investigate the invitro cross-linking of intermediate filament proteins. We will use techniques such as subcellular fractionation, gel electrophoresis, peptide mapping, acid hydrolysis, gel filtration, high performance liquid chromatography and immunoblotting to study the relationship between the pathological and normal fibrous proteins. The information obtained from the studies proposed might lead to further pathogenic clues as to the cause of this major cerebral lesion, and its relation to the disorder.