Selection Against Amyloid Precursor Protein (APP), using nucleic acid aptamers, holds therapeutic and diagnostic potentials for Alzheimers Disease (AD).
AD is a neuro-degenerative disease usually affecting individuals in the latter years of life; it is also the most common form of dementia. Common symptoms include short and long term memory loss, speech impediments, and gradually loss of bodily function. Even though AD was first diagnosed over 100 years ago, there exists no definitive cure for it, and diagnostics are based on expensive and time consuming imaging technologies and neuropsychological tests [1].
Amyloid beta is a protein that is key in the progression of AD, although the specifics of the mechanism are still being researched, the hypothesis that accumulation of this peptide leads to neural degeneration is considerably valid. An effective diagnostic tool, then, would be some sort of biomarker that could target and thus detect amyloid beta. Recent studies, conducted by Rahimi and Murakami of the David Geffen School of Medicine, however, investigated the practicality of targeting beta amyloid with such aptamers, but unfortunately, did not conclude with positive results [2].
The only information gleaned from this study was the fact that aptamer’s did show some affinity towards 40 and 42 Abeta concentrations. The conclusion however was that, “aptamers for oligomeric forms of amyloidogenic proteins cannot be selected due to high, non-specific affinity of oligonucleotides for amyloid fibrils” [2].
Figure I: The Abeta formation pathway [3]
Even though Abeta binding Aptamers weren’t exactly successful, a second prevalent protein, the precursor to Abeta in fact, also has high potential for diagnostic or perhaps even therapeutic research with aptamers. As seen in Figure I above, there is a stage in the Abeta formation pathway where APP is soluble and free of amyloid fibrils. If an aptamer, with high enough affinity for APP were to be found, it could be used to signal abnormally high levels of the same, or even halt the formation of Abeta fibrils in general: essentially, either eliminating Abeta plaque formation in general, or becoming a highly effective diagnostic tool.
APP is available for order through GenScript, catalogue number RP20165, for 189.00 dollars per milligram. [4]
[1] http://en.wikipedia.org/wiki/Alzheimer's_disease#Diagnosis
[2] Rahimi, F, et al. (2010), “RNA aptamers generated against oligomeric Abeta40 recognize common amyloid aptatopes with low specificity but high sensitivity”, David Geffen School of Medicine, Department of Neurobiology, Los Angeles, California.
[3] The Trafficking and Metabolism of Amyloid Precursor Protein (APP). Digital image. Coffee Break. NCBI, 15 Sept. 1999. Web. 25 Aug. 2010.
[4] "Beta Amyloid Peptides/ Beta Amyloid Peptide/ β Amyloid Peptide - GenScript." GenScript - Your Innovation Partner in Drug Discovery! Web. 31 Aug. 2010.
5 comments:
Good to see application of why an aptamer might be more successful with APP as opposed to Abeta; the figure provides a decent diagram of the process. The literature with APP/Abeta seems to point mainly to working with antibodies, so this might be a relatively novel idea. I would make some changes with your writing style to present more of a scientific voice, however. Thesaurus words (eg. gleamed) are not necessary. Tighten sentences by removing anything ambiguous sounding, and use less conjunctive adverbs ("..diagnostic tool,then, would be some.."). Also some grammatical/spelling errors (including the title D:), but overall cool topic and idea.
Nice abstract!
The paragraph that begins, "The only information gleaned," is confusing. What do you mean 40 and 42 concentrations? I'm probably just missing something.
I agree with Holli's suggestions to remove ambiguous phrases.
Do you have any safety concerns when working with such a protein? Just a little Abeta could seed fibril polymerizations ... read up on the safety precautions.
Also - my research focuses on protein aggregation. So - I could really use such an aptamer. Wanna collaborate? :)
Use more definitive terms (not more so, sort of, some sort ...)
What about their results were not positive? Did it not work?
Is there an idea as to one might be better than another?
@ holli: Thanks for the comment! Working on editing the abstract/proposal now with the stylistic suggestions you have made. I'll fix the title too :)
@ Gwen: Thank you! The 40 and 42 just refer to Abeta types. I'm not entirely sure what the specific differences between the two are. I'll look up the differences and get back to you. As far as safety precautions, I'm working with the precursor protein, not actual abeta, but I'll look those up as well.
And of course, I would love to collaborate! My proposal is really rudimentary, but I would be ecstatic if it helped you out in any way! Just let me know what I can do.
@Nia: The negative aspect of the research that I had mentioned was that the aptamers showed high affinity for non-specific amyloid fibrils, but not to the actual protein; thus the results were rather inconclusive.
As far as APP being a better target than Abeta, I can't say with any decisiveness that this is true. I simply thought that a diagnostic target in the middle of the pathogenic pathway (APP) would be better than one at the end. Such an aptamer could even lead to therapeutic solutions.
This is a nice project but we will have to biotinylate the target with the Pierce NHS Biotin kit prior to use since the target is not pre-functionalized and is tiny (3717 Da). Kit isn't difficult, but measuring effective biotinylation can be. You presented some ordering information, but to be complete, it is from GenScript, Cat #RP20165 and comes in 1mg quantities for $189.
Post a Comment