Identifying secreted mediators that drive the cognitive benefits of exercise holds great promise for the treatment of cognitive decline in ageing or Alzheimer’s disease (AD). Here, we show that irisin, the cleaved and circulating form of the exercise-induced membrane protein FNDC5, is sufficient to confer the benefits of exercise on cognitive function. Genetic deletion of Fndc5/irisin (global Fndc5 knock-out (KO) mice; F5KO) impairs cognitive function in exercise, ageing and AD. Diminished pattern separation in F5KO mice can be rescued by delivering irisin directly into the dentate gyrus, suggesting that irisin is the active moiety. In F5KO mice, adult-born neurons in the dentate gyrus are morphologically, transcriptionally and functionally abnormal. Importantly, elevation of circulating irisin levels by peripheral delivery of irisin via adeno-associated viral overexpression in the liver results in enrichment of central irisin and is sufficient to improve both the cognitive deficit and neuropathology in AD mouse models. Irisin is a crucial regulator of the cognitive benefits of exercise and is a potential therapeutic agent for treating cognitive disorders including AD.

识别出促进运动认知益处的分泌介质，对于治疗衰老或阿尔茨海默氏病 (AD) 引起的认知能力下降具有广阔的前景。在这里，我们证明鸢尾素（运动诱导膜蛋白 FNDC5 的裂解和循环形式）足以赋予运动对认知功能的益处。Fndc5 /irisin基因缺失（全局Fndc5基因敲除（KO）小鼠；F5KO）会损害运动、衰老和 AD 中的认知功能。F5KO小鼠中模式分离的减少可以通过将鸢尾素直接递送至齿状回来挽救，这表明鸢尾素是活性部分。在 F5KO 小鼠中，成年出生的齿状回神经元在形态、转录和功能上均存在异常。重要的是，通过肝脏中腺相关病毒过度表达向外周递送鸢尾素，从而提高循环鸢尾素水平，导致中枢鸢尾素富集，并足以改善 AD 小鼠模型的认知缺陷和神经病理学。鸢尾素是运动认知益处的重要调节剂，也是治疗包括 AD 在内的认知障碍的潜在治疗剂。