Supplemental Grant: Increased neutrophil function in Alzheimer's disease

补充补助金：阿尔茨海默病中中性粒细胞功能增强

• 批准号: 10284911
• 负责人: KENNETH E BERNSTEIN
• 金额: $ 33.4万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10284911
• 关键词: Abeta clearance; Address; Affect; Aging; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid beta-Protein; Amyloid deposition; Animals; Antigen-Antibody Complex; Bacterial Infections; Blood; Bone Marrow; Brain; Cell physiology; Cells; Chronic; Complex; Data; Dementia; Deposition; Disease; Disease Progression; Effectiveness; Excision; Family member; Floor; Funding; Glomerulonephritis; Goals; Grant; Human; Immune; Immune response; Immunology; Impaired cognition; Infection; Inflammation; Inflammatory; Institutes; Interest Group; Italy; Journals; Kidney; Link; Malignant Neoplasms; Medical center; Metabolic; Modeling; Mothers; Mus; Myeloid Cells; NADPH Oxidase; National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Disease; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Neurological Disorders and Stroke; Nervous System Trauma; Neurologic; Paper; Pathology; Pathway interactions; Peptidyl-Dipeptidase A; Phenotype; Physiological; Process; Publications; Publishing; Renin-Angiotensin System; Research Support; Role; Scientist; Senile Plaques; Serum; Time; Training; United States National Institutes of Health; Work; career; clinical application; clinical investigation; cognitive capacity; cognitive function; disorder control; immune function; inflammatory milieu; macrophage; monocyte; mouse model; neuroinflammation; neutrophil; novel; novel strategies; overexpression; parent grant; preservation; prevent; research study

A major factor contributing to neurologic injury in AD is a chronic inflammatory environment in the brain. Chronic inflammation often indicates an immune response unable to resolve an inflammatory challenge. An important question in AD is whether a means of reducing chronic neurologic inflammation can slow or arrest AD progression. Here, I present data showing that increasing the immune response is associated with a very marked reduction in the pathology of AD-like disease including cognitive decline. Specifically, mice that express increased amounts of ACE in macrophages (called ACE10/10) or neutrophils (called NeuACE) have an enhanced immune response to many different inflammatory challenges. When ACE10/10 mice were crossed onto an AD background, the resulting mice presented with far fewer brain Aβ plaques, less soluble serum and brain Aβ1-42, less chronic neuro-inflammation, and they retained cognitive capacity indistinguishable from non-AD control mice. In other words, enhancement of immune function in these mice significantly increased Aβ clearance and very much reduced the level of chronic inflammation. Here, and in the parent grant “Immune effects of ACE over-expression in neutrophils”, I present evidence that NeuACE neutrophils eliminate bacterial infections far more effectively than WT cells and also reduce deleterious inflammation in a model of glomerulonephritis. In both humans and mice, there are roughly 10 times more neutrophils than monocytes in circulating blood. This supplemental proposal is to use NeuACE mice, animals with elevated ACE in neutrophils, to study the role of neutrophils in protecting against the pathology of AD and preserving cognitive function. Specifically, I propose a comparison of increased ACE expression in macrophages vs. neutrophils (NeuACE) in AD. Given the greater number of neutrophils in blood compared to monocytes, I posit that NeuACE neutrophils will provide protection from the progressive pathology of AD. A positive finding would support my concept that a more effective immune response is advantageous in preventing deleterious chronic inflammation in AD. It would also point towards new approaches for treatment of this presently incurable disease.

导致AD中神经损伤的主要因素是脑组织中的慢性炎症环境。 个脑袋慢性炎症通常表明免疫反应无法解决炎症反应。 挑战. AD中的一个重要问题是减少慢性神经系统炎症的方法是否可以 减缓或阻止AD进展。在这里，我提出的数据表明，增加免疫反应是 与AD样疾病病理学（包括认知能力下降）的显著降低相关。 具体来说，在巨噬细胞（称为ACE 10/10）或中性粒细胞中表达增加量ACE的小鼠 （称为NeuACE）对许多不同的炎症挑战具有增强的免疫应答。当 将ACE 10/10小鼠与AD背景杂交，结果小鼠呈现出少得多的脑Aβ 斑块，可溶性血清和脑Aβ1-42较少，慢性神经炎症较少，并且他们保留了认知功能。 能力与非AD对照小鼠不可区分。换句话说，增强免疫功能， 这些小鼠显著增加了Aβ清除率，并大大降低了慢性炎症的水平。 在这里，以及在母基金“ACE在中性粒细胞过度表达的免疫效应”中，我提出了证据， NeuACE中性粒细胞比WT细胞更有效地消除细菌感染， 肾小球肾炎模型中的有害炎症。在人类和小鼠中， 循环血液中的中性粒细胞是单核细胞的两倍。本补充提案旨在使用NeuACE 小鼠，中性粒细胞中ACE升高的动物，研究中性粒细胞在保护免受 AD病理学和保持认知功能。具体来说，我提出了一个比较增加ACE AD中巨噬细胞相对于嗜中性粒细胞（NeuACE）的表达。考虑到体内的中性粒细胞数量较多， 与单核细胞相比，我认为中性粒细胞将提供保护， AD的病理学一个积极的发现将支持我的观点，即更有效的免疫反应是 在预防AD中有害的慢性炎症方面是有利的。它还将指向新的 治疗这种目前无法治愈的疾病。

项目成果

Overexpressed angiotensin-converting enzyme in neutrophils suppresses glomerular damage in crescentic glomerulonephritis

中性粒细胞中过度表达的血管紧张素转换酶抑制新月体肾小球肾炎的肾小球损伤

• DOI: 10.1152/ajprenal.00067.2022
• 发表时间: 2022
• 期刊: American Journal of Physiology-Renal Physiology
• 影响因子: 4.2
• 作者: Suguru Saito;Narihito Tatsumoto;Duo-Yao Cao;Nobuyuki Nosaka;Hiroshi Nishi;Daniel N Leal;Ellen Bernstein;Kenichi Shimada;Moshe Arditi;Kenneth E Bernstein;Michifumi Yamashita
• 通讯作者: Michifumi Yamashita

An ACE inhibitor reduces bactericidal activity of human neutrophils in vitro and impairs mouse neutrophil activity in vivo.

• DOI: 10.1126/scitranslmed.abj2138
• 发表时间: 2021-07-28
• 期刊: Science translational medicine
• 影响因子: 17.1