This study investigates whether disturbances in proteostasis, induced by increased translational errors, contribute to the accumulation of amyloid-beta (Aβ) and the formation of amyloid plaques in the brain, which are characteristic features of Alzheimer's disease. The researchers utilized a mouse model carrying the Rps9 D95N ribosomal ambiguity (ram) mutation, known to cause error-prone translation and a propensity for protein misfolding. These mice were crossed with humanized APP Knockin mice expressing various pathogenic mutations associated with Alzheimer's disease. The study aimed to determine if a misfolding-prone environment due to translational errors would exacerbate Aβ accumulation and plaque formation.
Despite the presence of the Rps9 D95N mutation, which induces a misfolding-prone environment, there was no significant effect on Aβ accumulation, plaque formation, or levels of phosphorylated Tau in any of the humanized APP Knockin lines. This suggests that perturbations in proteostasis due to translational errors do not significantly contribute to the development of Alzheimer's disease-related amyloid pathology.
The humanized APP Knockin mouse models used in this study were developed by genOway. These models express humanized amyloid precursor protein (APP) with different combinations of pathogenic mutations (wild-type, NL, NL-F, NL-G-F) that lead to a stepwise increase in Aβ accumulation and plaque formation. The Rps9 D95N ram mutation was introduced into these APP Knockin mice to assess the impact of increased translational errors on Aβ pathology.
Alzheimer's disease, Amyloid-beta, Proteostasis, Protein misfolding, Translational errors
Humanized Knockin mouse model, Rps9 D95N ram mutation, Error-prone translation, Protein aggregation analysis, Neuropathological assessment
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