Role of aggregation conditions and presence of small heat shock proteins on a [Beta] structure, stability and toxicity [electronic resource] /

by Lee, Sung Mun

Abstract (Summary)
Alzheimer's disease (AD) is a neurodegenerative disorder that is one of such diseases associated with protein aggregation. A [Beta] is the main protein component of senile plaques in AD, and is neurotoxic when aggregated. In particular, soluble oligomeric forms of A [Beta] are closely related to neurotoxicity. In this dissertation, we examine the differences in A [Beta] aggregation intermediates, and final structures formed when only a simple modification in A [Beta] aggregation conditions is made, the presence or absence of mixing during aggregation. We show that intermediates in the aggregation pathway show significantly different structural rearrangements. The protein stabilities of A [Beta] species show that spherical aggregates corresponding to the most toxic A [Beta] species change their structure the most rapidly in denaturant, and that in general, increased toxicity correlated with decreased aggregate stability. In Alzheimer's disease, even delaying A [Beta] aggregation onset or slowing its progression might be therapeutically useful, as disease onset is late in life. Small heat shock proteins (sHsps) may be useful for prevention of A [Beta] aggregation, since sHsps can interact with partly folded intermediate states of proteins to prevent incorrect folding and aggregation. In this research, several small heat shock proteins (sHsps) are tested to prevent A [Beta] aggregation and toxicity. sHsps used in this research are Hsp17.7, Hsp27, and Hsp20. All types of Hsp20, Hsp20-MBP, His-Hsp20 and His-Hsp20 without 11 residues in C-terminus, can prevent A [Beta]1-40 aggregation. Hsp20 also prevents A [Beta] toxicity in the same concentration ranges of it aggregation prevention activity. Hsp17.7 and Hsp27, however, can inhibit A [Beta]1-40 aggregation but not toxicity. A number of experiments to examine the mechanism of Hsp20 suggest that multivalent binding of sHsp to A [Beta] is necessary for the toxicity prevention activity. Conclusively, different A [Beta] incubation conditions in vitro can affect the rate of A [Beta] fibril formation, the morphology, the toxicity and the conformation of intermediates in the aggregation pathway. Hsp20 rather than other sHsps may be a useful molecular model for the drug design of the next generation of A [Beta] aggregation inhibitors to be used in the treatment of AD.
Bibliographical Information:


School:Texas A&M International University

School Location:USA - Texas

Source Type:Master's Thesis

Keywords:major chemical engineering conformation amyloid heat shock protein alzheimer s disease aggregation toxicity


Date of Publication:

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