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）包括急性谵妄和长期认知能力下降。 并发症在我们的老年人口中变得非常普遍，特别是在普通手术之后 超过 50% 的老年人在接受骨科骨折修复等手术后会出现谵妄。 手术通常对体弱的患者进行，包括患有痴呆症和精神错乱的患者。 痴呆症具有双向关系，尽管迄今为止它们仍然具有不同的病理生理学。 尚不清楚短暂的谵妄发作如何导致阿尔茨海默氏病的发展 我们已经建立并验证了临床相关的小鼠模型来研究相关痴呆症（ADRD）。 通过这个模型，我们发现手术对啮齿类动物的谵妄样病理的严重影响。 我们的初步结果表明，血脑屏障（BBB）功能和神经炎症标志物可以进行手术。 引起中枢神经系统 (CNS) 血管功能障碍，导致血管内约 58% 的周细胞迅速损失 中枢神经系统中的海马微血管在神经血管完整性和支持中发挥着关键作用。 与其他细胞类型的通讯和信号传导的最新研究。 周细胞在谵妄和谵妄中的作用 他们对长期认知衰退和 ADRD 的假定贡献仍然未知 该提案将开始 研究老年小鼠手术后周细胞长期丢失是否会导致长期认知能力下降 目的是确定周细胞在术后神经认知中的作用。 我们的中心假设是，衰老会延长手术后的周细胞功能障碍，从而导致持久的疾病。 该假设将在两个目标上进行检验：1）确定手术的影响- 诱导周细胞丢失对急性和长期神经炎症和神经元丢失的作用； 我们将以成人（3 个月）和老年人（18 个月大）为对象。 对雄性和雌性小鼠进行骨科手术，并评估周细胞、神经元损失和 我们还将用 PDGF-BB 治疗老年小鼠，以检测术后 24 小时和 3 个月的神经退行性标记物。 增强 PDGFRb 信号传导并促进周细胞募集，可能预防长期认知病理 后遗症，重点关注术后 3 个月的 PND 行为和神经退行性生物标志物。 该项目的结果将为确定新的具体目标奠定基础，以防止 PND 和减少 手术对患有 AD 或其他形式的痴呆症和神经退行性疾病的弱势老年人的影响。