| First Author | Maki T | Year | 2022 |
| Journal | Int J Mol Sci | Volume | 23 |
| Issue | 21 | PubMed ID | 36362046 |
| Mgi Jnum | J:334184 | Mgi Id | MGI:7385893 |
| Doi | 10.3390/ijms232113259 | Citation | Maki T, et al. (2022) APP Knock-In Mice Produce E22P-Abeta Exhibiting an Alzheimer's Disease-like Phenotype with Dysregulation of Hypoxia-Inducible Factor Expression. Int J Mol Sci 23(21) |
| abstractText | Alzheimer's disease (AD) is a progressive neurodegenerative disorder that requires further pathological elucidation to establish effective treatment strategies. We previously showed that amyloid beta (Abeta) toxic conformer with a turn at positions 22-23 is essential for forming highly toxic oligomers. In the present study, we evaluated phenotypic changes with aging in AD model App(NL-P-F/NL-P-F) (NL-P-F) mice with Swedish mutation (NL), Iberian mutation (F), and mutation (P) overproducing E22P-Abeta, a mimic of toxic conformer utilizing the knock-in technique. Furthermore, the role of the toxic conformer in AD pathology was investigated. NL-P-F mice produced soluble toxic conformers from an early age. They showed impaired synaptic plasticity, glial cell activation, and cognitive decline, followed by the accumulation of Abeta plaques and tau hyperphosphorylation. In addition, the protein expression of hypoxia-inducible factor (HIF)-1alpha was increased, and gene expression of HIF-3alpha was decreased in NL-P-F mice. HIF dysregulation due to the production of soluble toxic conformers may be involved in AD pathology in NL-P-F mice. This study could reveal the role of a highly toxic Abeta on AD pathogenesis, thereby contributing to the development of a novel therapeutic strategy targeting the toxic conformer. |
