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Studies on Amyloid Beta Peptide Aggregation and Its Modulation by Garlic Components: Relevance to Alzheimer’s Disease

Veer Bala, Gupta (2007) Studies on Amyloid Beta Peptide Aggregation and Its Modulation by Garlic Components: Relevance to Alzheimer’s Disease. PhD thesis, University of Mysore.

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The conformational changes in the proteins namely Aβ play an important role in neurodegeneration in AD, however little is known about the DNA conformational alteration. Further, the aggregation properties of Aβ strongly depend upon the amino acid sequence and their stereospecificity. In this perspective, we used Aβ(1-40) all-L, all-D and reverse peptides to understand the role of amino acid stereospecificity in modulating Aβ aggregation. Our data suggested that the aggregation and folding parameters of Aβ are stereospecific. There was differential aggregation pattern of both Aβ(1-40) all-L and all-D. Both enantiomers formed insoluble aggregates as a function of time with different fibrillar morphology. Aβ(1-40) all-L had longer fibrillar morphology, while Aβ(1-40) all- D had favored short fibrils, but reverse sequences (40-1) did not form fibrils. Also, the Lenantiomer of Aβ (1-40) was more prone for aggregation when compared to that of Denantiomer. This study clearly showed that the aggregation property of Aβ is coded in its sequence and depends upon the amino acid sequence and their stereospecificity. Further, the relationship between altered DNA topology and neurodegeneration in AD is not yet established. We demonstrated that the two enantiomers of Aβ40 alter conformation of ScDNA differently. Aβ40L induced Ψ−DNA conformation, which was similar in conformation to Z-DNA and this conformation, was reported in hippocampal region of AD brain. Aβ40D induced altered B-DNA. In the present investigation, the role of amino acid stereospecificity in DNA nicking was also studied. The D-enantiomer of Aβ40 was more potential in nicking ScDNA when compared to L-enantiomer of Aβ40 in a time and concentration dependent manner. However, Aβ(40-1) did not nick the DNA. The mechanism of nicking was initially through SSBs, which accumulated as DSBs, indicating that DSBs were formed as a result of cumulative SSBs in ScDNA. Moreover, both Aβ40L and D showed enhanced DNA nicking activity in presence of Mg2+ and Ca2+ whereas Zn inhibited Aβ40L/D from nicking DNA. The nuclease inhibitors like ATA and DEPC abolished DNA nicking activity of Aβ peptides. Based on the above results, we hypothesized that Aβ may induce toxicity through an independent non-apoptotic mechanism by behaving like a nuclease. Abstract The prevention of formation of Aβ oligomers/ toxic species by biomolecules is considered as one of the therapeutic approaches to AD. In this perspective, the efficacy of garlic and curcumin derivatives were evaluated. There was a dose-dependent inhibition of Aβ40 aggregation with increasing w/w ratio of garlic extract. Further, a component of garlic, SAC also showed inhibitory effect on Aβ aggregation and disaggregation of preformed fibrils. Hence, garlic could be used as an important bio-source for the development of potential anti-amyloidogenic agents. CG inhibited Cu2+ induced Aβ aggregation and also caused disaggregation of preformed fibrils. Thus, curcumin might not only function as an antioxidant and inhibitor of Aβ fibril formation directly but also indirectly by chelating metals such as Cu2+ The above study provided us an insight into the mechanism on the role of amino acid stereospecificity based aggregation pattern; non-apoptotic Aβ induced DNA nicking and neuro-neutraceutical property of garlic and curcumin derivatives. These findings provided us a molecular understanding of the neurodegeneration and neuroprotection in AD brain.

Item Type: Thesis (PhD)
Uncontrolled Keywords: Alzheimer's disease amyloid beta aggregation Anti-amyloidogenic activity Garlic Curcumin glucoside neurodegeneration
Subjects: 600 Technology > 01 Medical sciences > 09 Human Physiology
Divisions: Dept. of Biochemistry
Depositing User: Food Sci. & Technol. Information Services
Date Deposited: 07 May 2009 09:38
Last Modified: 07 May 2009 09:38
URI: http://ir.cftri.com/id/eprint/8932

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