Mice models of Alzheimer's disease (APP/PS1) typically experience cognitive decline with age. G6PD overexpressing mice (G6PD-Tg) exhibit better protection from age-associated functional decline including improvements in metabolic and muscle functions as well as reduced frailty compared to their wild-type counterparts. Importantly G6PD-Tg mice show diminished accumulation of DNA oxidation in the brain at different ages in both males and females. To further explore the potential benefits of modulating the G6PD activity in neurodegenerative diseases, triple transgenic mice (3xTg G6PD) were generated, overexpressing APP, PSEN1, and G6PD genes. The cognitive decline characteristic of APP/PS1 mice was prevented in 3xTg G6PD mice, despite similar amyloid-β (Aβ) levels in the hippocampus. This challenges the dominant hypothesis in Alzheimer's disease (AD) etiology and the majority of therapeutic efforts in the field, based on the notion that Aβ is pivotal in cognitive preservation.

中文翻译：

---

6 磷酸葡萄糖脱氢酶过度表达可挽救阿尔茨海默病双转基因 APP/PS1 小鼠模型的认知丧失


阿尔茨海默病（APP/PS1）小鼠模型通常会随着年龄的增长而出现认知能力下降。与野生型小鼠相比，G6PD 过表达小鼠 (G6PD-Tg) 表现出更好的保护作用，防止与年龄相关的功能衰退，包括改善代谢和肌肉功能以及减少虚弱。重要的是，G6PD-Tg 小鼠在不同年龄的雄性和雌性大脑中都显示出 DNA 氧化积累减少。为了进一步探索调节 G6PD 活性在神经退行性疾病中的潜在益处，产生了三重转基因小鼠 (3xTg G6PD)，它们过表达 APP、PSEN1 和 G6PD 基因。尽管海马中的淀粉样蛋白-β (Aβ) 水平相似，但 3xTg G6PD 小鼠阻止了 APP/PS1 小鼠的认知能力下降特征。这挑战了阿尔茨海默病 (AD) 病因学的主导假设以及该领域的大多数治疗工作，其基础是 Aβ 在认知保存中至关重要。