A hallmark of Alzheimer's disease (AD) is the accumulation of insoluble senile plaques in the brain.[1] The major component of the insoluble plaques is the amyloid-β peptide (Aβ) that is produced through cleavage of the amyloid-β precursor protein (APP).[2] It is well understood that once the monomeric Aβ is generated, it has the potential to aggregate into soluble oligomers and further into insoluble fibrils. Recently it has been proposed that early oligomers are the main toxic species in the aggregation cascade.[3] However, it has been shown that the formation of toxic early oligomers is inhibited by several endogenous plasma proteins, including albumin and transferrin (Tf). In this investigation we are focusing on the mechanism of inhibition of the Aβ early oligomerization by Tf. Specifically, we have targeted the early stages of Aβ aggregation using a deletion mutant of the Aβ peptide, i.e. the Aβ12-28 fragment, which selectively stabilizes the early Aβ oligomers. Self-association of this peptide was controlled by adding-NaCl to filtered monomeric Aβ samples and the effect of Tf inhibition on these aggregates was probed by 1H relaxation NMR experiments.[4-7] Our data shows that Tf directly targets intermediary Aβ oligomers via a coating mechanism.
1. Kirkitadze, M.D., Condron, M.M. and Teplow, D.B, JMB 2001 312;1103-1119.
2. Stefan F. Lichtenthaler and Christian Haass, JCI 2004 113(10);1384-1387.
3. Necula M., Kayed R., Milton, S. and Glabe C.G, JBC 2007 282(14);10311-10324.
4. Klement K., Wieligmann K., Meinhardt J., Hortschansky P., Richter W., and Fändrich M., JMB 2007 373;1321-1333.
5. Huang H, Milojevic J, Melacini G. J Phys Chem B. 2008 112(18):5795-802.
6. Milojevic J, Esposito V, Das R, Melacini G. JACS. 2007 129(14):4282-90.
7. Milojevic J, Esposito V, Das R, Melacini G. J Phys Chem B. 2006 110(41):20664-70. / Thesis / Master of Science (MSc)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/21624 |
| Date | 12 1900 |
| Creators | Raditsis, Annie Victoria |
| Contributors | Melacini, Giuseppe, Chemistry |
| Source Sets | McMaster University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis |
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