The long-term goal of this proposal is to understand the mechanisms involved in the fibrillogenesis of amyloid beta-protein (Abeta). This will be achieved by studying the formation of hydrophobic domain by aggregated / fibrillar amyloid beta-protein, and gelsolin-mediated inhibition of Abeta fibrillization. We have developed a diphenylhexatriene (DPH) fluorescence spectroscopic method for measuring fibrillar (f) Abeta, that is based on the hydrophobic domain formation by fAbeta. We hypothesize that formation of hydrophobic domain is the first event in Abeta fibrillogenesis, which may be prerequisite for nucleus formation. We propose that measuring Abeta fibrillization by DPH fluorescence spectroscopy may be an ideal tool to study the hydrophobic domain formation (nucleus) and its growth thereafter. We have reported earlier that extracellular gelsolin inhibits Abeta fibrillogenesis, and solubilizes Abeta fibrils. The regulation of Abeta fibrillogenesis by gelsolin will be studied by investigating the effect of gelsolin on hydrophobic domain formation and growth of Abeta filaments, binding-site of Abeta on gelsolin, neuroprotective action of gelsolin against Abeta toxicity, and comparing the gelsolin content in the blood and cerebrospinal fluid of patients with Alzheimer's disease, other neurological diseases, and age-matched non-demented control subjects. If our hypotheses are correct, then we will be able to detect the early stages of hydrophobic domain formation by fibrillar Abeta, and establish role of gelsolin / gelsolin-peptide(s) in the inhibition of Abeta fibrillogenesis.
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