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An RNA aptamer with potent affinity for a toxic dimer of amyloid β42 has potential utility for histochemical studies of Alzheimer’s disease
journal contributionposted on 19.01.2021, 02:28 authored by Kazuma Murakami, Yayoi Obata, Asa Sekikawa, Haruka Ueda, Naotaka Izuo, Tatsuya Awano, Keiji Takabe, Takahiko Shimizu, Kazuhiro Irie
© 2020 Murakami et al. 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-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.
This work was supported in part by Japan Society for the Promotion of Science KAKENHI Grants 26221202 (to K. I. and K. M.) 16H06194 (to K. M.), and 22603006 (to K. M.). The authors declare that they have no conflicts of interest with the contents of this article.
JournalJournal of Biological Chemistry
Pagination11p. (p. 4870-4880)
PublisherAmerican Society for Biochemistry and Molecular Biology Inc.
Rights StatementThe Author reserves all moral rights over the deposited text and must be credited if any re-use occurs. Documents deposited in OPAL are the Open Access versions of outputs published elsewhere. Changes resulting from the publishing process may therefore not be reflected in this document. The final published version may be obtained via the publisher’s DOI. Please note that additional copyright and access restrictions may apply to the published version.
Science & TechnologyLife Sciences & BiomedicineBiochemistry & Molecular BiologyAlzheimer diseaseamyloid-beta (AB)aggregationaptamercircular dichroism (CD)immunohistochemistryG-quadruplexoligomertransgenic miceRNABETA-PROTEINSECONDARY STRUCTUREOXIDATIVE STRESSOLIGOMERSNEUROTOXICITYAGGREGATIONMECHANISMSELECTIONSEQUENCEANTIBODYAnimalsHumansMiceAlzheimer DiseaseDisease Models, AnimalPeptide FragmentsImmunohistochemistryAptamers, NucleotideAmyloid beta-PeptidesPlaque, Amyloid