Role of pericytes in postoperative neurocognitive disorder during aging

摘要 围手术期神经认知障碍（PND）包括急性谵妄和长期认知功能下降。这些 并发症在我们的老年人群中变得非常普遍，特别是在普通外科手术后， 例如骨科骨折修复手术。谵妄影响超过50%的老年人整形后 外科手术，这通常是在虚弱的病人，包括那些预先存在的痴呆症。谵妄和 痴呆具有双向关系，尽管它们具有不同的病理生理学。至今， 目前尚不清楚短暂的谵妄发作如何导致阿尔茨海默病的发展， 相关性痴呆（ADRD）我们已经建立并验证了临床相关的小鼠模型，以研究 手术对啮齿类动物谵妄样病理的急性影响。在这个模型中，我们发现 血脑屏障（BBB）功能和神经炎症标志物。我们的初步结果表明， 在中枢神经系统（CNS）中诱导血管功能障碍，在中枢神经系统（CNS）中快速损失约58%的周细胞。 海马微血管中枢神经系统中的周细胞在神经血管完整性和支持 与其他细胞类型的通信和信号传递。阿尔茨海默病（AD）样本的最新研究 表明周细胞功能障碍可以促进神经退行性变。周细胞在谵妄中的作用， 他们对长期认知能力下降和ADRD的假定贡献仍然未知开始 研究老年小鼠手术后周细胞的长期损失是否易导致长期认知功能障碍， 衰退和神经退化。目的是明确周细胞在术后神经认知功能中的作用。 紊乱我们的中心假设是，手术后衰老的周细胞功能障碍导致持久的 神经血管疾病和痴呆。该假设将在2个目标中进行测试：1）确定手术的影响- 诱导的周细胞损失对急性和长期神经炎症和神经元损失的作用;和2）确定 周细胞在术后神经认知障碍中的作用我们将受试者成人（3个月）和老年人（18个月） 雄性和雌性小鼠进行整形外科手术，并评估周细胞、神经元损失和 术后24小时和3个月时的神经退行性标志物。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，以可能预防长期的认知病理学 后遗症，重点是术后3个月的PND行为和神经退行性生物标志物。总体而言， 该项目的结果将为确定新的和具体的目标提供基础，以预防PND和减少 手术对患有AD或其他形式的痴呆和神经变性的脆弱老年人的影响。

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.