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RSS FeedsAn RNA aptamer with potent affinity for a toxic dimer of amyloid {beta}42 has potential utility for histochemical studies of Alzheimer`s disease [Molecular Bases of Disease] (Journal of Biological Chemistry)

 
 

10 april 2020 11:02:31

 
An RNA aptamer with potent affinity for a toxic dimer of amyloid {beta}42 has potential utility for histochemical studies of Alzheimer`s disease [Molecular Bases of Disease] (Journal of Biological Chemistry)
 


Oligomers of ?-amyloid 42 (A?42), rather than fibrils, drive the pathogenesis of Alzheimer`s disease (AD). In particular, toxic oligomeric species called protofibrils (PFs) have attracted significant attention. Herein, we report RNA aptamers with higher affinity toward PFs derived from a toxic A?42 dimer than toward fibrils produced from WT A?42 or from a toxic, conformationally constrained A?42 variant, E22P-A?42. We obtained these RNA aptamers by using the preincubated dimer model of E22P-A?42, which dimerized via a linker located at Val-40, as the target of in vitro selection. This dimer formed PFs during incubation. Several physicochemical characteristics of an identified aptamer, E22P-AbD43, suggested that preferential affinity of this aptamer toward PFs is due to its higher affinity for the toxic dimer unit (KD = 20 6.0 nm) of A?42 than for less-toxic A?40 aggregates. Comparison of CD data from the full-length and random regions of E22P-AbD43 suggested that the preferential binding of E22P-AbD43 toward the dimer might be related to the formation of a G-quadruplex structure. E22P-AbD43 significantly inhibited the nucleation phase of the dimer and its associated neurotoxicity in SH-SY5Y human neuroblastoma cells. Of note, E22P-AbD43 also significantly protected against the neurotoxicity of WT A?42 and E22P-A?42. Furthermore, in an AD mouse model, E22P-AbD43 preferentially recognized diffuse aggregates, which likely originated from PFs or higher-order oligomers with curvilinear structures, compared with senile plaques formed from fibrils. We conclude that the E22P-AbD43 aptamer is a promising research and diagnostic tool for further studies of AD etiology.


 
21 viewsCategory: Biochemistry
 
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