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

特异性抑制 PDE4B 对衰老相关认知衰退的影响

• 批准号: BB/R019401/1
• 负责人: Steven Clapcote
• 金额: $ 56.46万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FR019401%2F1
• 关键词: Effects; specific; inhibition; PDE4B; senescence

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.

认知老化是一个渐进的、持续的、但随着年龄增长而发生的认知功能变化的终身过程。在健康的老年大脑中，变化导致认知能力下降，影响老年人日常生活活动的表现，如驾驶汽车，并增加老年人患阿尔茨海默病等神经退行性疾病的脆弱性。使用一种名为rolipram的药物治疗，这种药物可以降低四种酶-PDE 4A，PDE 4 B，PDE 4C和PDE 4D-的活性，已被证明可以在老年（>18个月大）小鼠中诱导各种有益效果，包括学习和记忆的改善。不幸的是，当咯利普兰在人体中进行测试时，它引起了严重的恶心和呕吐，可能是由抑制PDE 4D引起的。为了开发一种治疗与年龄相关的认知能力下降的方法，这种方法具有咯利普兰的潜在益处，但没有其不可接受的副作用，我们通过改变年轻成年（12周龄）小鼠的PDE 4 B基因来特异性抑制它们的PDE 4 B。我们最近报道说，这些PDE 4 B抑制的小鼠增强了学习和记忆，大脑中神经细胞之间的连接更多更强，并且在大脑中称为海马体的部分产生了更多新的神经细胞，这对学习和记忆很重要。该项目将发现改变的PDE 4 B基因是否对年龄（18个月大）有类似的有益影响。人类也有PDE 4 B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影响。由于不可能改变人类患者的PDE 4 B基因，我们还评估了一种名为A-33的选择性PDE 4 B抑制药物对老年小鼠的认知作用。A-33之前已经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在老年小鼠中具有类似的作用。我们的研究结果将帮助我们决定PDE 4 B抑制是否值得作为与年龄相关的认知能力下降的新治疗方法。

项目成果

Genetically altered animal models for ATP1A3-related disorders.

• DOI: 10.1242/dmm.048938
• 发表时间: 2021-10-01
• 期刊: Disease models & mechanisms
• 影响因子: 4.3
• 作者: Ng HWY;Ogbeta JA;Clapcote SJ
• 通讯作者: Clapcote SJ

PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies.

• DOI: 10.1016/j.biopsych.2021.12.017
• 发表时间: 2022-08-15
• 期刊: Biological psychiatry
• 影响因子: 10.6

PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice and Fruit Flies

PDZD8 破坏导致人类、小鼠和果蝇认知障碍

• DOI: 10.17863/cam.80327
• 发表时间: 2022
• 作者: Al-Amri A