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        Ben Keshet
            e-mail: keshet1@umbc.edu
            410-455-3437

            B.S Physics (2004) The Hebrew University of Jerusalem
            PhD student,  advisor: Theresa Good
            Chemical & Biochemical Engineering
            University of Maryland Baltimore County (UMBC)
Research 

β amyloid peptide (Aβ) is believed to play a key role in the mechanism of Alzheimer’s disease (AD).  Aβ tends to associate and form amyloid fibrillar aggregates rich in β-sheet content.  A variety of evidence indicates that Aβ aggregates are toxic in vitro, and the presence of certain Aβ oligomers species appear to be correlated with AD pathology in vivo.  An early ‘Aβ hypothesis’ postulated that AD was the consequence of neuron death induced by insoluble deposits of large Aβ fibrils.  However, newer findings indicate that the small soluble Aβ intermediate oligomers are more neurotoxic than the fibrils.  Yet, the structure of the toxic Aβ species and the pathway by which it forms are unknown. 

An alternative explanation - Can size and concetration explain some of the differnce in toxicity betwen Aβ fibril and intermediate?
Our experimental data imply that the toxic intermediate and fibril share the same molecular level structure, suggesting that the intermediate is a small structural unit similar to the fibril.  This result may imply that the intermediate appears more toxic than the fibril due to its higher mobility and higher concentration, and not due to differences in structure specific interactions of the different aggregated species.  We developed a simplified model, which can explain the differences in biological activity between the toxic intermediate and the mature fibrils, using a diffusion-limited reaction model and geometry considerations.  

Elucidation of key amino acids in the interactions of β-Amyloid aggregates with neurons

We elucidated the binding sites of small molecular weight toxicity inhibitors, as means to explore residues and surfaces on Aβ that are associated with toxicity.  Our overall goal is to identify molecular level details of the interaction of Aβ with neurons.  We hypothesize that some of the inhibitors share the same binding sites, and that the common binding loci are significant for toxicity.  To that end, computational docking was performed to predict the binding of several small molecular weight inhibitors to the Aβ fibril.  We tested the predications experimentally using single residue Aβ mutants, or Aβ chemically modified at specific amino acids.  We found that docking predicted two common binding sites for all the inhibitors.  Experimentally, we found that at least two inhibitors; congo red and myricetin, which are structurally dissimilar, share the same two binding sites on Aβ.  Three additional inhibitors; curcumin, nicotine and melatonin, seem to interact with Aβ at at one the same sites.  Our finding may suggest that the common sites are important for the Aβ interaction with cells.  Elucidating the amino acids on the Aβ fibril surface that are important for the interaction with cells could provide us with a better understanding of the mechanism of Aβ neurotoxicity, and may be valuable in developing novel therapeutics for Alzheimer’s disease.