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Effects of (+) MK-801 (dizocilpine) and non-coding RNA on aggregation of beta-amyloid peptides linked to Alzheimer's Disease
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Coombs, Susan Elizabeth
RNA aptamers selected for two disparate targets, the nicotinic acetylcholine receptor (Ulrich et al., 1998) and beta-amyloid (Abeta) peptides (Ylera et al., 2002), share a consensus sequence (Gadalla & Hess, 2006). The RNA aptamers selected for the nicotinic acetylcholine receptors fell into two classes. Class 1 aptamers inhibited the receptor and, in the presence of an activator of the receptor, Class 2 aptamers alleviated the inhibition. The short consensus sequence of Class 1 aptamers retained this activity (Sivaprakasam et al., 2010). Gadalla and Hess (2006) recognized that the same consensus sequence occurred in the RNA aptamers selected for the Abeta(1-40) peptide by Ylera et al. (2002). Some organic compounds that bind to the acetylcholine receptor, and affect its function, were assigned to either Class 1 or Class 2 (Hess et al., 2000). (+) MK-801 (dizocilpine) is a Class 1 compound. In the work reported here, the effects of (+) MK-801 and of memantine on the aggregation pathway of Abeta(1-40) and Abeta(1-42) peptides have been examined using the Thioflavin T fluorescence assay, nuclear magnetic resonance spectroscopy, and electron microscopy. Memantine is FDA-approved for the treatment of mild-moderate Alzheimer’s Disease. Both compounds accelerated the initial formation of beta-sheets by the Abeta peptides, (+) MK-801 more rapidly than memantine. But in the presence of either compound a decrease in the fluorescence signal followed the initial rise, a decrease that was not observed when they were absent. The decrease may represent an abruptly formed, insoluble aggregated state, rather than a return to the initial non-beta-sheet state. In the absence of either compound, the fluorescence signal indicating beta-sheet formation reaches a plateau. NMR spectra of the soluble peptides in the presence and absence of (+) MK-801 were compared to the fluorescence measurements and showed a similar difference for the initial phase. However, no return to the monomeric form was observed, possibly suggesting that the decrease in fluorescence in the Thioflavin T assay represented the formation of insoluble aggregates. Consistent with this interpretation, electron microscopy of the insoluble peptides formed over time showed a more rapid rate of formation of clumped fibrils in the presence of (+) MK-801 than in its absence. Thus, as observed by three different techniques, (+) MK-801 and memantine increase the rate of Abeta peptide aggregation as compared to the aggregation that occurs in their absence. This raises a question: What is the effect on patients of long-term treatment with memantine? Is there an explanation for the observation that led to this study, the shared consensus sequence between aptamers selected for two different targets? This cannot yet be answered. In this study, it was recognized that the consensus sequences of the two classes of RNA aptamers targeting the acetylcholine receptor are complementary in the 5’-3’ and 3’-5’ directions. Is this of biological significance? The selection of two classes of aptamers is not limited to this excitatory receptor. Fluorinated RNA aptamers that target the inhibitory GABAA (alpha1, beta2, gamma2) receptor have been selected (Cui et al., 2004). They also fell into two classes: Class 1 inhibited the receptor and, in the presence of GABA, Class 2 alleviated picrotoxin (Ramakrishan & Hess, 2005) inhibition. Exploration of the observations might lead to an understanding of the shared consensus sequence between the two targets, the nicotinic acetylcholine receptor and the Abeta peptides.
memantine; MK-801; nicotinic acetylcholine receptor; Molecular biology; Pharmacology; RNA aptamers; Neurosciences; Alzeheimer's Disease; Beta-amyloid
Oswald, Robert Edward
Nicholson, Linda K.; Feigenson, Gerald W.; Weiland, Gregory Arthur
Ph. D., Pharmacology
Doctor of Philosophy
dissertation or thesis