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

摘要/摘要 阿尔茨海默氏病（AD）是老年人中最常见的痴呆形式， 随着世界人口老龄化，发病率正在上升。没有有效的治疗方法。流行病学 研究已经显示AD和心力衰竭（HF）以及AD的病理生理学之间的密切联系， HF是惊人的相似，但这种联系的生物学基础仍不清楚。线索可能就在 运动的影响，预防HF和AD的干预。我们最近发现了SALTe （运动中的衰老相关LncRNA转录），心脏中上调的长非编码RNA 从老年小鼠，HF，并下调运动。SALTe是保守的，并在 内皮细胞在心脏内皮细胞（ECs）中，SALTe过表达诱导细胞衰老 并且减少血管生成，而其抑制减少衰老并改善血管生成。SALTe 通过PARP 9介导的NAD+代谢赋予这些作用。有趣的是，我们发现 在心脏功能受损的老年小鼠的大脑中升高。运动减少SALTe， 老年小鼠的大脑和心脏。此外，从APP/PS1开始，海马中的SALTe增加 转基因AD小鼠我们假设，SALTe作为一种共同的机制，有助于 HF和AD的发展和运动通过抑制SALTe预防或减缓AD的发展。 为了验证这些假设，我们建议：1。研究SALTe在AD中的作用及其预防， 锻炼，2。阐明SALTe调节AD的机制。我们预计， 这些研究将为SALTe在AD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SALTe的临床相关方法，以促进AD的认知功能， 老年人 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