PDF(Pubmed)
Abstract：
Accumulation of hyper-phosphorylated tau and amyloid beta (Aβ) are key pathological hallmarks of Alzheimer\'s disease (AD). Increasing evidence indicates that in the early pre-clinical stages of AD, phosphorylation and build-up of tau drives impairments in hippocampal excitatory synaptic function, which ultimately leads to cognitive deficits. Consequently, limiting tau-related synaptic abnormalities may have beneficial effects in AD. There is now significant evidence that the hippocampus is an important brain target for the endocrine hormone leptin and that leptin has pro-cognitive properties, as activation of synaptic leptin receptors markedly influences higher cognitive processes including learning and memory. Clinical studies have identified a link between the circulating leptin levels and the risk of AD, such that AD risk is elevated when leptin levels fall outwith the physiological range. This has fuelled interest in targeting the leptin system therapeutically. Accumulating evidence supports this possibility, as numerous studies have shown that leptin has protective effects in a variety of models of AD. Recent findings have demonstrated that leptin has beneficial effects in the preclinical stages of AD, as leptin prevents the early synaptic impairments driven by tau protein and amyloid β. Here we review recent findings that implicate the leptin system as a potential novel therapeutic target in AD.
摘要：
过度磷酸化tau和淀粉样β(Aβ)的积累是阿尔茨海默病(AD)的关键病理标志。越来越多的证据表明，在AD的临床早期阶段，磷酸化和tau的积累驱动海马兴奋性突触功能受损，最终导致认知缺陷。因此,限制tau相关的突触异常可能在AD中具有有益作用。现在有重要的证据表明，海马是内分泌激素瘦素的重要大脑目标，瘦素具有促进认知的特性，因为突触瘦素受体的激活显着影响高级认知过程，包括学习和记忆。临床研究已经确定了循环瘦素水平与AD风险之间的联系。因此，当瘦素水平超出生理范围时，AD风险升高。这促进了在治疗上靶向瘦素系统的兴趣。越来越多的证据支持这种可能性，大量研究表明，瘦素在多种AD模型中具有保护作用。最近的研究结果表明，瘦素在AD的临床前阶段具有有益的作用。因为瘦素可以防止由tau蛋白和β淀粉样蛋白驱动的早期突触损伤。在这里，我们回顾了最近的发现，这些发现暗示瘦素系统是AD的潜在新治疗靶标。
