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dc.contributorGood, Theresa A.
dc.contributorShantz, Daniel F.
dc.creatorLee, Sung Mun
dc.date.accessioned2006-08-16T19:08:37Z
dc.date.accessioned2017-04-07T19:51:46Z
dc.date.available2006-08-16T19:08:37Z
dc.date.available2017-04-07T19:51:46Z
dc.date.created2003-05
dc.date.issued2006-08-16
dc.identifier.urihttp://hdl.handle.net/1969.1/3905
dc.description.abstractAlzheimer??s disease (AD) is a neurodegenerative disorder that is one of such diseases associated with protein aggregation. Aβ is the main protein component of senile plaques in AD, and is neurotoxic when aggregated. In particular, soluble oligomeric forms of Aβ are closely related to neurotoxicity. In this dissertation, we examine the differences in Aβ aggregation intermediates, and final structures formed when only a simple modification in Aβ 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 Αβ species show that spherical aggregates corresponding to the most toxic Αβ 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 Aβ 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 Αβ 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 Aβ 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 Aβ1-40 aggregation. Hsp20 also prevents Aβ toxicity in the same concentration ranges of it aggregation prevention activity. Hsp17.7 and Hsp27, however, can inhibit Αβ1-40 aggregation but not toxicity. A number of experiments to examine the mechanism of Hsp20 suggest that multivalent binding of sHsp to Aβ is necessary for the toxicity prevention activity. Conclusively, different Aβ incubation conditions in vitro can affect the rate of Aβ 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 Aβ aggregation inhibitors to be used in the treatment of AD.
dc.language.isoen_US
dc.publisherTexas A&M University
dc.subjectAlzheimer's disease
dc.subjectamyloid
dc.subjectaggregation
dc.subjectheat shock protein
dc.subjecttoxicity
dc.subjectconformation
dc.titleRole of aggregation conditions and presence of small heat shock proteins on abeta structure, stability and toxicity
dc.typeBook
dc.typeThesis


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