Currais Antonio, Goldberg Joshua, Farrokhi Catherine, Chang Max, Prior Marguerite, Dargusch Richard, Daugherty Daniel, Armando Aaron, Quehenberger Oswald, Maher Pamela, Schubert David
The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Department of Medicine, University of California San Diego, CA 92093-0601, USA.
Aging (Albany NY). 2015 Nov;7(11):937-55. doi: 10.18632/aging.100838.
Because age is the greatest risk factor for sporadic Alzheimer's disease (AD), phenotypic screens based upon old age-associated brain toxicities were used to develop the potent neurotrophic drug J147. Since certain aspects of aging may be primary cause of AD, we hypothesized that J147 would be effective against AD-associated pathology in rapidly aging SAMP8 mice and could be used to identify some of the molecular contributions of aging to AD. An inclusive and integrative multiomics approach was used to investigate protein and gene expression, metabolite levels, and cognition in old and young SAMP8 mice. J147 reduced cognitive deficits in old SAMP8 mice, while restoring multiple molecular markers associated with human AD, vascular pathology, impaired synaptic function, and inflammation to those approaching the young phenotype. The extensive assays used in this study identified a subset of molecular changes associated with aging that may be necessary for the development of AD.
由于年龄是散发性阿尔茨海默病（AD）的最大风险因素，基于与老年相关的脑毒性进行的表型筛选被用于研发强效神经营养药物J147。鉴于衰老的某些方面可能是AD的主要病因，我们推测J147对快速衰老的SAMP8小鼠的AD相关病理具有疗效，并且可用于确定衰老对AD的一些分子影响。我们采用了一种全面且综合的多组学方法来研究老年和年轻SAMP8小鼠的蛋白质和基因表达、代谢物水平及认知情况。J147减少了老年SAMP8小鼠的认知缺陷，同时将与人类AD、血管病变、突触功能受损及炎症相关的多个分子标志物恢复至接近年轻表型的水平。本研究中使用的广泛检测确定了一组与衰老相关的分子变化，这些变化可能是AD发病所必需的。
