Ageing increases susceptibility to neurodegenerative disorders, such as Alzheimer’s disease (AD). Serum levels of sclerostin, an osteocyte-derived Wnt–β-catenin signalling antagonist, increase with age and inhibit osteoblastogenesis. As Wnt–β-catenin signalling acts as a protective mechanism for memory, we hypothesize that osteocyte-derived sclerostin can impact cognitive function under pathological conditions. Here we show that osteocyte-derived sclerostin can cross the blood–brain barrier of old mice, where it can dysregulate Wnt–β-catenin signalling. Gain-of-function and loss-of-function experiments show that abnormally elevated osteocyte-derived sclerostin impairs synaptic plasticity and memory in old mice of both sexes. Mechanistically, sclerostin increases amyloid β (Aβ) production through β-catenin–β-secretase 1 (BACE1) signalling, indicating a functional role for sclerostin in AD. Accordingly, high sclerostin levels in patients with AD of both sexes are associated with severe cognitive impairment, which is in line with the acceleration of Αβ production in an AD mouse model with bone-specific overexpression of sclerostin. Thus, we demonstrate osteocyte-derived sclerostin-mediated bone–brain crosstalk, which could serve as a target for developing therapeutic interventions against AD.

衰老会增加对神经退行性疾病的易感性，例如阿尔茨海默病 (AD)。硬化素（一种骨细胞衍生的 Wnt-β-连环蛋白信号传导拮抗剂）的血清水平随着年龄的增长而增加，并抑制成骨细胞生成。由于 Wnt-β-连环蛋白信号传导充当记忆的保护机制，我们假设骨细胞衍生的硬化蛋白可以影响病理条件下的认知功能。在这里，我们发现骨细胞衍生的硬化蛋白可以穿过老年小鼠的血脑屏障，从而使 Wnt-β-连环蛋白信号传导失调。功能获得和功能丧失实验表明，骨细胞衍生的硬化蛋白异常升高会损害雌雄老年小鼠的突触可塑性和记忆力。从机制上讲，硬化蛋白通过 β-连环蛋白-β-分泌酶 1 (BACE1) 信号传导增加 β 淀粉样蛋白 (Aβ) 的产生，表明硬化蛋白在 AD 中的功能作用。因此，两性AD患者的高硬化蛋白水平与严重的认知障碍相关，这与骨特异性硬化蛋白过度表达的AD小鼠模型中Aβ产生的加速一致。因此，我们证明了骨细胞衍生的硬化素介导的骨脑串扰，这可以作为开发针对 AD 的治疗干预措施的目标。