Identification and drug-induced reversion of molecular signatures of Alzheimer´s disease onset and progression in AppNL-G-F, AppNL-F and 3xTg-AD mouse models (RNA-seq: WT/NLGF). Identification and drug-induced reversion of molecular signatures of Alzheimer´s disease onset and progression in AppNL-G-F, AppNL-F and 3xTg-AD mouse models (RNA-seq: WT/NLGF)

Alzheimer's disease (AD) is the most common form of dementia. Over fifty years of intense research have revealed many key elements of the biology of this neurodegenerative disorder. However, our understanding of the molecular bases of the disease is still incomplete, and the available medical treatments for AD are mainly symptomatic and hardly effective. Indeed, the robustness of biological systems have revealed that the modulation of a single target is unlikely to yield the desired outcome, and we should move from gene-centric to systemic therapeutic strategies. Here, we present the complete characterization of three murine models of AD at different stages of the disease (i.e. onset, progression and advanced). To identify genotype-to-phenotype relationships, we combine the cognitive assessment of these mice with histological analyses and a full transcriptional and protein quantification profiling from hippocampus. Comparison between the gene and protein expression trends observed in AD progression and physiological ageing exposed certain commonalities, such as the upregulation of microglial and inflammation markers. However, although there is an accelerated ageing in AD models, there are other factors specifically associated with A_ pathology. Despite the clear correlation between mRNA and protein levels of the dysregulated genes, we discovered a few proteins whose abundance increases with AD progression, while the corresponding transcript levels remain stable. Indeed, we show that at least two of these proteins, namely lfit3 and Syt11, co-localize with A_ plaques in the brain. Finally, we derive specific A_-related molecular AD signatures, and we look for drugs able to globally revert them. We found two NSAIDs (dexketoprofen and etodolac) and two anti-hypertensives (penbutolol and bendroflumethiazide) that overturn the cognitive impairment in AD mice while reducing A_ plaques in the hippocampus and partially restoring the physiological levels of AD signature genes to wild-type levels. Overall design: We analyzed the gene expression changes in the hippocampus of 6 months old AppNL-G-F mice treated with Etodolac (50 mg/kg), dexketoprofen (15 mg/kg), fenoprofen (50 mg/kg) and bendroflumethiazide (20 mg/kg) and the corresponding controls (vehicle-treated AppNL-G-F and Appwt/wt mice). We analyzed four mice per condition.

阿尔茨海默病（Alzheimer's disease, AD）是最常见的痴呆类型。五十余年来的深入研究已揭示了这一神经退行性疾病生物学机制的诸多关键环节。然而，我们对该病分子基础的认知仍不完整，现有AD治疗手段仅能改善症状且疗效有限。事实上，生物系统的稳健性表明，单一靶点的调控难以取得预期疗效，我们应从以基因为中心的治疗策略转向系统性治疗方案。本研究完整表征了三种处于疾病不同阶段（即发病期、进展期及晚期）的AD小鼠模型。为解析基因型-表型关联，我们将小鼠的认知功能评估结果与组织学分析、海马体的全转录组与蛋白质组定量分析相结合。通过对比AD进展与生理性衰老过程中基因与蛋白的表达趋势，我们发现了若干共性特征，例如小胶质细胞与炎症标志物的上调表达。尽管AD模型存在加速衰老的表型，但仍存在其他与A_病理特异性相关的因素。尽管失调基因的mRNA与蛋白水平存在显著相关性，但我们仍发现了少数蛋白，其丰度随AD进展而升高，而对应转录本的水平却保持稳定。研究证实，其中至少两种蛋白——lfit3与Syt11——可在脑内与A_斑块共定位。最后，我们推导得到了与A_相关的特异性AD分子特征谱，并筛选能够全局逆转该特征谱的药物。最终发现两种非甾体抗炎药（Non-Steroidal Anti-Inflammatory Drugs, NSAIDs）：右酮洛芬与依托度酸，以及两种抗高血压药物：喷布洛尔与苄氟噻嗪，它们可逆转AD小鼠的认知损伤，同时减少海马体中的A_斑块，并将AD特征基因的生理表达水平部分恢复至野生型小鼠水平。总体实验设计：我们分析了经依托度酸（50 mg/kg）、右酮洛芬（15 mg/kg）、非诺洛芬（50 mg/kg）及苄氟噻嗪（20 mg/kg）处理的6月龄AppNL-G-F小鼠海马体的基因表达变化，并以相应对照组（赋形剂处理的AppNL-G-F小鼠与Appwt/wt小鼠）作为参照。每组设置4只小鼠进行实验。