Role of pericytes in postoperative neurocognitive disorder during aging

周细胞在衰老过程中术后神经认知障碍中的作用

• 批准号: 10510133
• 负责人: Ting Yang
• 金额: $ 32.2万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-02 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10510133
• 关键词: Acute; Address; Adult; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; American; Amyloid beta-Protein; Animals; Arousal; Astrocytes; Attention; Awareness; Basement membrane; Behavior; Behavior Disorders; Behavioral; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Vessels; Blood flow; Cells; Cerebrovascular system; Chronic; Clinic; Cognitive; Cognitive deficits; Communication; Delirium; Dementia; Development; Diagnosis; Disease; Elderly; Endothelial Cells; Etiology; Female; Foundations; Functional disorder; Future; Genes; Hippocampus (Brain); Histology; Human; Impaired cognition; Impairment; Incidence; Measures; Modeling; Mus; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neuroimmune; Neurologic; Newly Diagnosed; Operative Surgical Procedures; Orthopedic Surgery; Orthopedics; Pathology; Patients; Pericytes; Perioperative; Plasma; Play; Population; Postoperative Period; Procedures; Process; Prognosis; Protocols documentation; Public Health; Research; Research Personnel; Risk; Risk Factors; Rodent; Role; Sampling; Signal Transduction; Testing; Tibial Fractures; Trauma; Vascular Diseases; age group; aged; alanine aminopeptidase; blood-brain barrier function; bone fracture repair; brain endothelial cell; cell type; cerebral capillary; clinically relevant; cognitive function; dementia risk; executive function; experience; foot; male; mouse model; neurocognitive disorder; neuroinflammation; neuron loss; neuropsychiatry; neurovascular; neurovascular unit; next generation; novel; platelet-derived growth factor BB; postoperative delirium; prevent; programs; protective effect; recruit; spatial memory; transcriptomics; vascular contributions; vasoconstriction

ABSTRACT Perioperative neurocognitive disorders (PNDs) include acute delirium and long-lasting cognitive decline. These complications have become highly prevalent in our geriatric population, especially following common surgical procedures such as orthopedic fracture repairs. Delirium impacts over 50% of older adults after orthopedic surgery, which is often performed in frail patients including those with pre-existing dementia. Delirium and dementia have bidirectional relationships even though they have distinct pathophysiologies. To-date it remains unknown how a transient episode of delirium can contribute to the development of Alzheimer’s Disease and related dementia (ADRD). We have established and validated a clinically relevant mouse model to study the acute impact of surgery on delirium-like pathology in rodents. With this model we found significant changes in blood-brain barrier (BBB) function and neuroinflammatory markers. Our Preliminary Results indicate that surgery induces vascular dysfunction in the central nervous system (CNS), with a rapid loss of ~58% of pericytes in the hippocampal microvasculature. Pericytes in the CNS play key roles in neurovascular integrity and supporting communication and signaling with other cell types. Recent studies from Alzheimer’s disease (AD) samples demonstrated that pericyte dysfunction can promote neurodegeneration. The role of pericytes in delirium and their putative contribution to long-lasting cognitive decline and ADRD remain unknown This proposal will begin to investigate whether protracted loss of pericytes after surgery in aged mice predisposes to long-term cognitive decline and neurodegeneration. The Objective is to define the role of pericytes in postoperative neurocognitive disorders. Our Central Hypothesis is that aging prolongs pericytes dysfunction after surgery leading to enduring neurovascular disorders and dementia. The hypothesis will be tested in 2 aims: 1) Identify the effects of surgery- induced pericyte loss on acute and long-term neuroinflammation and neuronal loss; and 2) Determine the role of pericytes in postoperative neurocognitive disorder. We will subject adult (3-months) and aged (18-mo-old) male and female mice to orthopedic surgery, and evaluate changes in pericytes, neuronal loss, and neurodegenerative markers at 24 hr and 3 months after surgery. We will also treat aged mice with PDGF-BB to boost PDGFRb signaling and promote pericytes recruitment to possibly prevent long-lasting cognitive pathology sequalae, focusing on PNDs behaviors and neurodegenerative biomarkers 3 months after surgery. Overall, results from this project will provide a foundation to identify novel and specific targets to prevent PNDs and curtail the effects of surgery on vulnerable older adults with AD or other forms of dementia and neurodegeneration.

抽象的 围手术期神经认知障碍（PND）包括急性del妄和持久的认知能力下降。这些 并发症在我们的老年人群中变得非常普遍，尤其是在常见外科手术后 诸如骨科断裂维修之类的程序。 del妄影响了骨科之后的50％以上的老年人 手术通常是在脆弱的患者中进行的，包括患有痴呆症的患者。 del妄和 痴呆症具有双向关系，即使它们具有不同的病理生理。迄今为止它仍然存在 未知del妄的短暂发作如何有助于阿尔茨海默氏病的发展和 相关痴呆（ADRD）。我们已经建立并验证了临床相关的小鼠模型，以研究 手术对啮齿动物中ir妄样病理学的急性影响。通过此模型，我们发现了重大变化 血脑屏障（BBB）功能和神经炎症标记。我们的初步结果表明手术 诱导中枢神经系统（CNS）诱导血管功能障碍，迅速损失约58％ 海马微举行。中枢神经系统的周细胞在神经血管完整性和支持中起关键作用 与其他单元类型的通信和信号传导。阿尔茨海默氏病（AD）样本的最新研究 证明周细胞功能障碍可以促进神经退行性。周细胞在ir妄和 他们对长期认知能力下降和adrd的假定贡献仍然未知，这一建议将开始 调查在老年小鼠手术后是否受保护的周细胞丧失，易感长期认知 衰落和神经变性。目的是定义周细胞在术后神经认知中的作用 疾病。我们的中心假设是，衰老在手术后延长了周细胞功能障碍，导致持久 神经血管疾病和痴呆症。该假设将以2个目的进行检验：1）确定手术的影响 - 急性和长期神经炎症和神经元丧失诱发周细胞丧失； 2）确定角色 术后神经认知障碍中周细胞的。我们将受到成人（3个月）和老化（18个月大） 雄性和雌性小鼠进行骨科手术，并评估周细胞的变化，神经元丧失和 术后24小时和手术后3个月的神经退行性标记。我们还将用PDGF-BB治疗老年小鼠 增强PDGFRB信号传导并促进周细胞募集，以防止持久的认知病理 Sequalae，重点是PNDS行为和神经退行性生物标志物，手术后3个月。全面的， 该项目的结果将为识别新颖和特定的目标提供基础，以防止PND和减少 手术对具有AD或其他形式的痴呆和神经变性的脆弱老年人的影响。