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: 10407460
• 负责人: Uwe Rudolph
• 金额: $ 38.85万
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10407460
• 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).

项目总结/摘要 老年患者大手术后一个相对常见的并发症是术后 认知功能障碍（POCD），可持续数天至数周，在极少数情况下甚至数月 手术后。在>60岁的患者中，26%的患者在1周后显示出POCD的迹象，10%的患者在3周后显示出POCD的迹象。 个月，而对照组在两个时间点均为3%。POCD被发现与增加 依赖社会转移支付，过早离开劳动力市场的风险增加， mortality. POCD潜在的分子和细胞机制尚不清楚，这也是为什么 POCD在老年患者中的发生率高于年轻患者。随着年龄的增长，POCD会增加，年龄- 相关的认知功能障碍可能是一个危险因素。在啮齿类动物中已经证明， 齿状回（DG）门中生长抑素阳性中间神经元导致DG和CA 3的过度兴奋 并且与年龄相关的认知功能障碍有关。然而，损失之间的因果关系 生长抑素阳性的中间神经元在DG门和认知功能障碍尚未得到证实。 因此，我们希望通过化学遗传学抑制和基因消融这些神经元，以证明这些神经元的功能。 变化足以引起认知功能障碍。此外，我们还想扭转这些局面， 缺陷，并确定这种逆转的分子和细胞基础。据报道，在老年大鼠中， GABAA受体α5-阳性变构调节剂（α5-PAM）不能改善年轻大鼠的认知功能， 这与α5-PAM降低老年大鼠海马DG和CA 3的过度兴奋性一致。 也有报道称，慢性间歇性丙泊酚可改善与年龄相关的认知功能障碍， 这种作用的分子和细胞底物尚未确定。我们想验证一个假设， 异丙酚的这种作用是通过持续增加含有α5的GABAA受体的表达介导的， 细胞表面。我们还想鉴定表达含α5的GABAA的神经元细胞群， 这些受体介导了认知能力的提高。此外，我们还想测试化学遗传学是否 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起 慢性间歇性丙泊酚的认知增强作用。最后，我们将研究术后（即， 剖腹手术后）认知功能损害可以通过慢性间歇性丙泊酚预防或减轻 或GABAA受体α5-PAM。总之，我们将研究年龄背后的分子和细胞机制- 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一个 为制定预防和/或治疗老年患者POCD的策略提供了途径。未来的临床试验 可以使用慢性间歇性丙泊酚或潜在的α5-PAM，例如目前正在研究的新型α5-PAM， 在一个项目中， 由NIH Blueprint Neurotherapeutics Network（1UH 2NS 101856 -01）资助。

项目成果

Reduction of Postoperative Cognitive Deficits in Aged Mice by Chronic Intermittent Propofol.

慢性间歇性丙泊酚减少老年小鼠术后认知缺陷。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Nagarajan,Rajasekar;Lyu,Jinrui;Kambali,Maltesh;Wang,Muxiao;Pearce,RobertA;Rudolph,Uwe
• 通讯作者: Rudolph,Uwe

Selective inhibition of somatostatin-positive dentate hilar interneurons induces age-related cellular changes and cognitive dysfunction.

• DOI: 10.1093/pnasnexus/pgad134
• 发表时间: 2023-05
• 期刊: PNAS NEXUS
• 作者: Lyu, Jinrui;Nagarajan, Rajasekar;Kambali, Maltesh;Wang, Muxiao;Rudolph, Uwe
• 通讯作者: Rudolph, Uwe