Whole transcriptome analysis of brain hippocampal tissue from young and old senescence-accelerated prone SAMP8 mice treated with control diet and J147-containing diet

AD drug discovery has rarely been addressed in the context of aging even though sporadic AD accounts for 99% of the cases. Phenotypic screens based upon old age-associated brain toxicities were used to develop the potent AD drug candidate J147. Here, we hypothesized that J147 would be effective against both brain aging and AD-associated pathology in rapidly aging SAMP8 mice, a model for early sporadic AD. An inclusive and integrative multi-omics approach was used to investigate protein expression, RNA expression, metabolite levels as well as cognition in old and young SAMP8 mice. J147 not only reduced the cognitive deficits and associated metabolic changes observed in old SAMP8 mice, it restored the levels of multiple markers of AD, vascular pathology, synaptic function, and inflammation to those approaching the young phenotype. Our data show that a drug candidate selected upon the basis of preventing old age-related brain toxicities also reduces AD-associated pathology.

尽管99%的阿尔茨海默病（Alzheimer's Disease, AD）病例为散发性病例，但针对衰老背景下的AD药物研发相关研究却鲜有开展。基于老年相关脑毒性的表型筛选，被用于开发强效AD候选药物J147。本研究假设，J147可在快速老化SAMP8小鼠——一种早发性散发性AD模型——中同时对抗脑衰老与AD相关病理损伤。本研究采用全面整合的多组学（multi-omics）策略，对年轻与老年SAMP8小鼠的蛋白质表达、RNA表达、代谢物水平及认知功能开展了系统性探究。J147不仅改善了老年SAMP8小鼠的认知缺陷及其伴随的代谢紊乱，还将AD、血管病理、突触功能与炎症的多种标志物水平恢复至接近年轻小鼠的表型状态。本研究数据表明，基于预防老年相关脑毒性筛选得到的候选药物，同样能够减轻AD相关病理损伤。