Effects of specific inhibition of PDE4B on senescence-associated cognitive decline

认知衰老是一个随着人们年龄的增长，认知功能发生逐渐、持续、但高度可变的变化的终身过程。在健康的老年人大脑中，这种变化会导致认知能力下降，影响老年人日常生活活动的表现，比如开车，并增加患阿尔茨海默病等神经退行性疾病的风险。用一种叫做罗利普兰的药物进行治疗，可以降低四种酶家族（PDE4A、PDE4B、PDE4C和PDE4D）的活性，这种药物已被证明对老年（bb - 18个月）小鼠产生了各种有益的影响，包括学习和记忆的改善。不幸的是，当罗利普兰在人体中进行测试时，它引起了严重的恶心和呕吐，可能是由PDE4D的抑制引起的。为了开发一种治疗与年龄相关的认知衰退的方法，这种方法具有罗利普兰的潜在益处，但没有其不可接受的副作用，我们通过改变年轻成年（12周大）小鼠的PDE4B基因来特异性抑制PDE4B。我们最近报道说，这些pde4b抑制小鼠的学习和记忆能力增强了，大脑中神经细胞之间的联系越来越强，在大脑中被称为海马体的部分产生了更多的新神经细胞，海马体对学习和记忆很重要。该项目将发现PDE4B基因的改变是否对年龄（18个月）有类似的有益影响。人类也有PDE4B酶，因此抑制它可能对受认知能力下降影响的老年人产生类似的效果。由于不可能改变人类患者的PDE4B基因，我们还评估了一种名为a -33的选择性PDE4B抑制药物对老年小鼠的认知影响。a -33先前在创伤性脑损伤的大鼠模型中显示出认知益处，因此我们认为它可能对老年小鼠有类似的作用。我们的研究结果将帮助我们确定PDE4B抑制是否值得作为一种治疗与年龄相关的认知衰退的新方法。

Cognitive ageing is a lifelong process of gradual, ongoing, yet highly variable changes in cognitive function that occurs as people get older. In the healthy aged brain, changes lead to cognitive decline that affects the performance of activities of daily living, such as driving a car, in the elderly and increase vulnerability to the development of neurodegenerative conditions like Alzheimer's disease. Treatment with a drug called rolipram, which reduces the activity of a family of four enzymes - PDE4A, PDE4B, PDE4C and PDE4D - has been shown to induce a variety of beneficial effects in aged (>18-month-old) mice, including improvements in learning and memory. Unfortunately, when rolipram was tested in humans, it caused severe nausea and vomiting, likely caused by inhibition of PDE4D. To develop a treatment for age-related cognitive decline that has the potential benefits of rolipram but without its unacceptable side-effects, we specifically inhibited PDE4B in young adult (12-week-old) mice by altering their PDE4B gene. We recently reported that these PDE4B-inhibited mice have enhanced learning and memory, more and stronger connections between nerve cells in the brain, and more generation of new nerve cells in a part of the brain called the hippocampus that is important for learning and memory. This project will find out whether the altered PDE4B gene has similar beneficial effects in age (18-month-old). Humans also have the PDE4B enzyme, so inhibiting it could have similar effects in elderly people affected by cognitive decline. Since it is not possible to alter the PDE4B gene in human patients, we also assess the cognitive effects of a selective PDE4B-inhibiting drug called A-33 in the aged mice. A-33 has previously shown cognitive benefits in a rat model of traumatic brain injury, so we think it may have similar effects in aged mice. Our results will help us decide whether PDE4B inhibition is worth pursuing as a new treatment for age-related cognitive decline.