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

Oligomers of β-amyloid 42 (Aβ42), 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 Aβ42 dimer than toward fibrils produced from WT Aβ42 or from a toxic, conformationally constrained Aβ42 variant, E22P–Aβ42. We obtained these RNA aptamers by using the preincubated dimer model of E22P–Aβ42, 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 Aβ42 than for less-toxic Aβ40 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 Aβ42 and E22P–Aβ42. Furthermore, in an AD mouse model, E22P–AbD4...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Neurobiology Source Type: research

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