Cellular mechanisms for age-related cognitive dysfunction and its pharmacological reversal: a strategy towards prevention and treatment of postoperative cognitive deficits in elderly patients

年龄相关认知功能障碍的细胞机制及其药理学逆转：预防和治疗老年患者术后认知缺陷的策略

• 批准号: 10152619
• 负责人: Uwe Rudolph
• 金额: $ 38.89万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10152619
• 关键词: Activities of Daily Living; Address; Age; Age-Years; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amnesia; Amyloid beta-Protein; Anesthesia procedures; Animals; Attenuated; Brain; Caspase; Cell surface; Cells; Chronic; Clinical Research; Clinical Trials; Cognition; Cognitive; Cognitive deficits; Complication; Dependence; Development; Dose; Flumazenil; Functional disorder; Funding; Future; General Anesthesia; Goals; Hippocampus (Brain); Human; Impaired cognition; Impairment; Incidence; Inflammation; Interneuron function; Interneurons; Intervention; Investigation; Knowledge; Laparotomy; Learning; Link; Mediating; Memory; Modeling; Molecular; Mus; Neurons; Operative Surgical Procedures; Patients; Performance; Pharmacology; Physiological; Physiological Processes; Play; Population; Postoperative Period; Predisposition; Prevention; Process; Propofol; Rattus; Recovery; Reporting; Risk; Risk Factors; Rodent; Role; Severities; Signal Transduction; Social Work; Somatostatin; Testing; Therapeutic; Therapeutic Intervention; Time; Transgenic Mice; United States National Institutes of Health; age related; aged; aging population; cell type; cognitive enhancement; cognitive function; cognitive performance; dentate gyrus; executive function; experimental study; gamma-Aminobutyric Acid; health care service utilization; improved; insight; mild cognitive impairment; mortality; mouse model; novel; novel strategies; older patient; payment; positive allosteric modulator; post-operative cognitive dysfunction; premature; prevent; preventive intervention; receptor; social; young adult

PROJECT SUMMARY / ABSTRACT A relatively frequent complication after major surgery in elderly patients is the development of postoperative cognitive dysfunction (POCD), which can persist for several days to weeks, and in rare instances even months postoperatively. In patients >60 years of age, 26% display signs of POCD after 1 week, and 10% after 3 months, compared to 3% in controls at both time points. POCD was found to be associated with increased dependency on social transfer payments, increased risk of leaving the labor market prematurely and increased mortality. The molecular and cellular mechanisms underlying POCD are unknown, as is the reason why POCD occurs more frequently in elderly patients than in younger patients. As POCD increases with age, age- related cognitive dysfunction likely represents a risk factor. It has been shown in rodents that loss of somatostatin-positive interneurons in the dentate gyrus (DG) hilus results in hyperexcitability of DG and CA3 and is associated with age-related cognitive dysfunction. However, a cause-effect relationship between loss of somatostatin-positive interneurons in the DG hilus and cognitive dysfunction has not been demonstrated so far. We therefore want to chemogenetically inhibit and genetically ablate these neurons to demonstrate that these changes are sufficient to elicit cognitive dysfunction. Moreover, we want to pharmacologically reverse these deficits and identify the molecular and cellular basis for this reversal. It has been reported that in aged rats but not in young rats a GABAA receptor α5-positive allosteric modulator (α5-PAM) improves cognitive function, which is in line with an α5-PAM reducing the hyperexcitability of DG and CA3 of the hippocampus in aged rats. It has also been reported that chronic intermittent propofol improves age-related cognitive dysfunction, but the molecular and cellular substrates of this action have not been identified. We want to test the hypothesis that this action of propofol is mediated by a sustained increase in expression of α5-containing GABAA receptors on the cell surface. We also want to identify the neuronal cell population expressing the α5-containing GABAA receptors that mediate this improvement of cognition. Furthermore, we want to test whether chemogenetic inhibition of somatostatin-positive interneurons in the DG hilus of young adult mice is sufficient to elicit the cognitive-enhancing effect of chronic intermittent propofol. Finally, we will study whether postoperative (i.e., post laparotomy) impairment of cognitive function can be prevented or reduced by chronic intermittent propofol or a GABAA receptor α5-PAM. In summary, we will study molecular and cellular mechanisms underlying age- related postoperative cognitive dysfunction and its reversal. The proposed studies are expected to provide an avenue for the development of strategies to prevent and/or treat POCD in elderly patients. Future clinical trials could use chronic intermittent propofol or potentially α5-PAMs, such as novel α5-PAMs that are currently being developed for the indication of mild cognitive impairment due to Alzheimer's disease in humans in a project funded by the NIH Blueprint Neurotherapeutics Network (1UH2NS101856-01).

项目摘要 /摘要 老年患者大手术后相对较常见的并发症是术后发展 认知功能障碍（POCD），可以持续几天到几周，在极少数情况下甚至几个月 子术。在> 60岁> 60岁的患者中，1周后26％显示POCD的迹象，而10％后3％ 几个月，在两个时间点，对照组为3％。发现POCD与增加有关 依赖社会转移付款，增加劳动力市场过早离开的风险并增加 死亡。 POCD上下的分子和细胞机制是未知的，原因也是如此 在老年患者中，POCD比在年轻患者中更频繁。随着POCD随着年龄的增长而增加，年龄 - 相关的认知功能障碍可能代表了危险因素。在啮齿动物中已显示出损失 齿状回（DG）Hilus中的生长抑素阳性中间神经元导致DG和CA3的过度兴奋性 并且与年龄相关的认知功能障碍有关。但是，丧失之间的原因效应关系 到目前为止，尚未证明DG Hilus和认知功能障碍中的生长抑素阳性中间神经元。 因此，我们希望在化学上抑制和遗传烧毁这些神经元，以证明这些神经元 变化足以引起认知功能障碍。此外，我们想在药物上扭转这些 缺陷并确定这种逆转的分子和细胞基础。据报道，在老鼠中 在年轻大鼠中，GABAA受体α5阳性变构调节剂（α5-PAM）改善了认知功能， 这与α5-PAM一致，可降低老年大鼠海马的DG和CA3的过度兴奋。 还据报道，慢性间歇性提案改善了与年龄有关的认知功能障碍，但是 该作用的分子和细胞底物尚未鉴定。我们想检验以下假设 这种提案的作用是由含α5的GABAA受体表达的持续增加来介导的 细胞表面。我们还想确定表达含α5的GABAA的神经元细胞群 调解这种认知改善的接收者。此外，我们要测试是否 抑制年轻小鼠DG Hilus中生长抑素阳性的中间神经元足以引起 慢性间歇性建议的认知增强作用。最后，我们将研究术后是否（即 剖腹手术后）认知功能的损害可以通过慢性间歇性建议来预防或减少 或GABAA受体α5-PAM。总而言之，我们将研究年龄 - 年龄的分子和细胞机制 相关的术后认知功能障碍及其逆转。预计拟议的研究将提供 制定预防和/或治疗POCD的策略的途径。未来的临床试验 可以使用慢性间歇性建议或潜在的α5-PAM，例如当前正在的新型α5-PAM 由于人类在一个项目中的阿尔茨海默氏病而导致的轻度认知障碍指示 由NIH蓝图神经疗法网络（1UH2NS101856-01）资助。