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

摘要/摘要

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