A Long Noncoding RNA SALTe Links Heart Failure to Alzheimer's Disease

摘要/摘要 阿尔茨海默病(AD)是老年人最常见的痴呆形式，其 随着世界人口的老龄化，发病率正在增加。目前还没有有效的治疗方法。流行病学 研究表明阿尔茨海默病和心力衰竭之间有很强的联系，而且阿尔茨海默病和 HF是惊人的相似，然而这种联系的生物学基础仍然不清楚。线索可能隐藏在 运动的影响，这是一种同时预防心力衰竭和AD的干预措施。我们最近发现了盐岩 (运动中的衰老相关lncRNA转录本)，一种在心脏上调的长非编码RNA 从衰老的小鼠，HF，并通过运动下调。盐是保守的，并且在 内皮细胞。在心脏内皮细胞(ECs)中，盐分过表达诱导细胞衰老 抑制血管生成，延缓衰老，促进血管生成。盐类 这些作用是通过PARP9介导的NAD+代谢来实现的。有趣的是，我们发现了盐分 在心功能受损的老年小鼠脑组织中升高。运动中减少盐分 衰老小鼠的大脑和心脏。此外，APP/PS1增加了海马区的盐分 转基因AD小鼠。我们假设盐作为一种共同的机制作用于 心衰和阿尔茨海默病的发展和运动通过抑制盐分来预防或减缓阿尔茨海默病的发展。 为了验证这些假设，我们建议：1.研究盐在AD中的作用及其预防 2.阐明盐分调节AD的机制。我们预计这些 研究将为盐分在阿尔茨海默病的病理生理学中的作用提供新的线索。此外，这些研究 将建立针对盐分的临床相关方法来促进AD和 上了年纪的人。 1

Summary / Abstract Alzheimer’s disease (AD) is the most common form of dementia in older individuals and its incidence is increasing as the world population ages. There is no effective treatment. Epidemiological studies have shown a strong link between AD and heart failure (HF) and the pathophysiology of AD and HF is strikingly similar, however the biological basis for this link remains unclear. A clue may lie in the effects of exercise, an intervention that protects against both HF and AD. We recently identified SALTe (Senescence Associated LncRNA Transcript in exercise), a long noncoding RNA upregulated in the heart from aged mice, HF, and downregulated by exercise. SALTe is conserved and highly expressed in endothelial cells. In cardiac endothelial cells (ECs), SALTe overexpression induced cellular senescence and reduced angiogenesis, while its inhibition reduced senescence and improved angiogenesis. SALTe conferred these effects through PARP9-mediated NAD+ metabolism. Intriguingly, we found that SALTe was elevated in brains of aged mice, whose cardiac function were impaired. Exercise reduced SALTe in the brain and heart from aged mice. Moreover, SALTe was increased in the hippocampus from APP/PS1 transgenic AD mice. We hypothesize that SALTe works as a common mechanism contributes to the development of HF and AD and exercise prevents or slows the development of AD by inhibiting SALTe. To test these hypotheses, we propose to: 1. Examine the role of SALTe in AD and its prevention by exercise, and 2. Elucidate the mechanisms by which SALTe regulates AD. We anticipate that these studies will shed new lights into the role of SALTe in the pathophysiology of AD. Moreover, these studies will establish clinically relevant approaches targeting SALTe to promote cognitive function in AD and aging individuals. 1