Down syndrome (DS) individuals, by the age of 40s, are at increased risk to develop Alzheimer-like dementia, with deposition in brain of senile plaques and neurofibrillary tangles. Our laboratory recently demonstrated the disturbance of PI3K/AKT/mTOR axis in DS brain, prior and after the development of Alzheimer Disease (AD). The aberrant modulation of the mTOR signalling in DS and AD age-related cognitive decline affects crucial neuronal pathways, including insulin signaling and autophagy, involved in pathology onset and progression. Within this context, the therapeutic use of mTOR-inhibitors may prevent/attenuate the neurodegenerative phenomena. By our work we aimed to rescue mTOR signalling in DS mice by a novel rapamycin intranasal administration protocol (InRapa) that maximizes brain delivery and reduce systemic side effects. Ts65Dn mice were administered with InRapa for 12 weeks, starting at 6 months of age demonstrating, at the end of the treatment by radial arms maze and novel object recognition testing, rescued cognition. The analysis of mTOR signalling, after InRapa, demonstrated in Ts65Dn mice hippocampus the inhibition of mTOR (reduced to physiological levels), which led, through the rescue of autophagy and insulin signalling, to reduced APP levels, APP processing and APP metabolites production, as well as, to reduced tau hyperphosphorylation. In addition, a reduction of oxidative stress markers was also observed. These findings demonstrate that chronic InRapa administration is able to exert a neuroprotective effect on Ts65Dn hippocampus by reducing AD pathological hallmarks and by restoring protein homeostasis, thus ultimately resulting in improved cognition. Results are discussed in term of a potential novel targeted therapeutic approach to reduce cognitive decline and AD-like neuropathology in DS individuals.

中文翻译：

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鼻内雷帕霉素可改善唐氏综合症小鼠模型中的阿尔茨海默样认知衰退

唐氏综合征 (DS) 个体在 40 多岁时患阿尔茨海默病样痴呆的风险增加，大脑中会沉积老年斑和神经原纤维缠结。我们实验室最近证实了阿尔茨海默病 (AD) 发展前后 DS 脑中 PI3K/AKT/mTOR 轴的紊乱。DS 和 AD 与年龄相关的认知衰退中 mTOR 信号的异常调节会影响与病理发作和进展有关的关键神经元通路，包括胰岛素信号和自噬。在这种情况下，mTOR 抑制剂的治疗用途可以预防/减轻神经退行性现象。通过我们的工作，我们旨在通过一种新的雷帕霉素鼻内给药方案 (InRapa) 来挽救 DS 小鼠中的 mTOR 信号传导，该方案可最大限度地提高大脑输送并减少全身副作用。Ts65Dn 小鼠在 6 个月大时开始服用 InRapa 12 周，证明在治疗结束时通过径向臂迷宫和新的物体识别测试，恢复了认知。在 InRapa 之后对 mTOR 信号传导的分析表明，在 Ts65Dn 小鼠海马中 mTOR 受到抑制（降低到生理水平），这通过拯救自噬和胰岛素信号传导导致 APP 水平、APP 加工和 APP 代谢物产生降低，如以及，以减少 tau 过度磷酸化。此外，还观察到氧化应激标志物的减少。这些发现表明，长期 InRapa 给药能够通过减少 AD 病理特征和恢复蛋白质稳态来对 Ts65Dn 海马发挥神经保护作用，从而最终改善认知。