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).

项目概要/摘要 老年患者大手术后相对常见的并发症是术后出现 认知功能障碍 (POCD)，可能持续数天至数周，在极少数情况下甚至数月 术后 60 岁以上的患者中，26% 在 1 周后出现 POCD 症状，10% 在 3 周后出现 POCD 症状。 月，相比之下，对照组在两个时间点的患病率均为 3%。 对社会转移支付的依赖，过早离开劳动力市场的风险增加， POCD 的分子和细胞机制尚不清楚，其原因也是未知的。 POCD 在老年患者中比年轻患者更常见，因为 POCD 随着年龄的增长而增加。 相关的认知功能障碍是一个危险因素，在啮齿类动物中已被证明可能会丧失认知功能。 齿状回 (DG) 门中的生长抑素阳性中间神经元导致 DG 和 CA3 过度兴奋 然而，与年龄相关的认知功能障碍之间存在因果关系。 DG门中的生长抑素阳性中间神经元与认知功能障碍的关系迄今为止尚未得到证实。 因此，我们希望通过化学遗传学方法抑制和基因消融这些神经元，以证明这些神经元 此外，我们希望通过药物来逆转这些变化。 据报道，在老年大鼠中存在这种缺陷并确定这种逆转的分子和细胞基础。 GABAA 受体 α5 阳性变构调节剂 (α5-PAM) 不会改善幼鼠的认知功能， 这与 α5-PAM 降低老年大鼠海马 DG 和 CA3 过度兴奋的作用一致。 还有报道称，慢性间歇性丙泊酚可改善与年龄相关的认知功能障碍，但 我们想要检验这一假设的分子和细胞底物。 丙泊酚的这种作用是通过持续增加含 α5 的 GABAA 受体的表达来介导的。 我们还想鉴定表达含 α5 GABAA 的神经元细胞群。 此外，我们想测试化学遗传学是否会介导这种认知改善。 抑制年轻成年小鼠 DG 门中的生长抑素阳性中间神经元足以引发 最后，我们将研究术后（即，长期间歇性丙泊酚）是否具有认知增强作用。 慢性间歇性异丙酚可以预防或减少剖腹手术后认知功能损伤 或 GABAA 受体 α5-PAM 总之，我们将研究年龄相关的分子和细胞机制。 相关的术后认知功能障碍及其逆转。 制定预防和/或治疗老年患者 POCD 的策略的途径。 可以使用慢性间歇性丙泊酚或潜在的 α5-PAM，例如目前正在研发的新型 α5-PAM 在一个项目中开发用于指示人类阿尔茨海默病引起的轻度认知障碍 由 NIH 蓝图神经治疗网络 (1UH2NS101856-01) 资助。