Details

Autor(en) / Beteiligte

• Izuo, Naotaka
• Murakami, Kazuma
• Fujihara, Yoshitaka
• Maeda, Masahiro
• Saito, Takashi
• Saido, Takaomi C.
• Irie, Kazuhiro
• Shimizu, Takahiko

Titel

An App knock-in mouse inducing the formation of a toxic conformer of Aβ as a model for evaluating only oligomer-induced cognitive decline in Alzheimer's disease

Ist Teil von

• Biochemical and biophysical research communications, 2019-07, Vol.515 (3), p.462-467

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2019

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Irie and colleagues identified a “toxic conformer”, which possesses a turn structure at positions 22-23, among various conformations of Aβ and have been reporting its potent oligomeric capacity and neurotoxicity. This toxic conformer was detected in the brains of AD patients and AD model mice (Tg2576 line), and passive immunization targeting this conformer ameliorated the cognitive dysfunction in an AD model. In this study, we developed a novel AD mouse model (AppNL-P-F/NL-P-F) with Swedish mutation (NL), Iberian mutation (F), and mutation (P) overproducing E22P-Aβ, a mimic of the toxic conformer, utilizing the knock-in technique that well recapitulates the Aβ pathology of AD patients in mice and avoids the artificial phenotype observed in transgenic-type model mice. We confirmed that AppNL-P-F/NL-P-F mice produce Aβ by ELISA and accumulate senile plaques by immunohistochemistry at eight months of age. In WB, we observed a potential trimer band and high molecular-weight oligomer bands without a monomeric band in the TBS-soluble fraction of AppNL-P-F/NL-P-F mice at six months of age. In the novel object recognition test, cognitive impairment was observed at six months of age in these mice. These findings suggest that the toxic conformer of Aβ induces cognitive dysfunction mediated by its oligomer formation in this mouse brain. AppNL-P-F/NL-P-F mice may be a useful model for evaluating Aβ oligomer-induced cognitive impairment in AD and will aid in exploring therapeutic targets for AD pathology. •A new knock-in-type AD model overproducing a toxic conformer of Aβ was developed.•Oligomers derived from the toxic conformer were detected at six months of age.•Senile plaque deposition started from eight months of age in this model.•Cognitive decline was observed before the presence of the plaques in this model.•This model is useful for analyzing Aβ oligomer-mediated cognitive decline.