Role of Mast cells in Alzheimer's Disease

肥大细胞在阿尔茨海默病中的作用

基本信息

批准号：
10374113
负责人：
GUO-PING SHI
金额：
$ 61.79万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-15 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10374113
关键词：
APP-PS1 Adoptive Transfer Affect Alzheimer like pathology Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease diagnosis Alzheimer&apos s disease pathology Alzheimer&apos s disease patient American Amyloid beta-Protein Anti-Allergic Agents Antibodies Antibody Therapy Astrocytes Behavior Binding Bispecific Antibodies Blood - brain barrier anatomy Cause of Death Cell surface Cells Cerebral cortex Chymase Clinical Cognitive Data Dementia Deposition Disease Disease Progression Dose Elderly Endothelial Cells Engineering Enzyme-Linked Immunosorbent Assay Event Extravasation Fc Receptor Genetic Goals Hippocampus (Brain)Histamine Human Hypersensitivity IL6 gene IgE IgE Receptors Imaging Techniques Impaired cognition In Vitro Infiltration Inflammatory Interferon Type II Link Memory Loss Metabolism Microglia Mus Neurons Non-Prescription Drugs Pathogenesis Pathogenicity Pathologic Patients Peptide Hydrolases Phagocytes Pharmacology Plasma Play Production Proto-Oncogene Protein c-kit Role Sampling Senile Plaques Site Source Stains Synapses T-Lymphocyte TFRC gene TNF gene Techniques Technology Testing Thalamic structure Therapeutic Tissue Extracts Treatment Efficacy Tryptase Water Xolair abeta deposition activation product allergic response anti-IgE antibody detection base behavior test blood-brain barrier permeabilization brain endothelial cell brain tissue cerebral amyloidosis chemokine cytokine disability drug withdrawal extracellular improved inhibitor mass spectrometric imaging mast cell neuron loss neurotoxic novel therapeutics omalizumab prevent reconstitution therapeutic evaluation

项目摘要

Mast cells (MCs) play important roles in allergic responses. Recent studies suggest that MCs are also essential to other inflammatory diseases by releasing inflammatory cytokines, chemokines, and the MC- specific proteases chymase and tryptase after degranulation. Pharmacological inactivation of MCs prevents or slows disease progression. Alzheimer’s disease (AD) is the most common cause of dementia and disability in the elderly. It is the sixth leading cause of death in the U.S., affecting more than 5 million Americans alone, according to the Alzheimer’s Association. One definitive diagnosis of AD is based on the presence of extracellular deposition of neurotoxic β-amyloid (Aβ) into senile plaques. Human AD brains have elevated protease expression, neuronal death and synapse loss, blood-brain barrier (BBB) leakage, and activation of inflammatory cells such as microglia, astrocytes, and T cells. MCs also present in human AD brains, mainly in the hippocampus, cerebral cortex, and thalamus, but studies have yet to test whether these cells participate directly in the pathogenesis or serve merely as another inflammatory hallmark. Our preliminary data demonstrated that the plasma levels of MC activator IgE and MC granular contents tryptase and histamine were elevated in patients with early stage AD, indicating enhanced systemic MC activation. Anti-tryptase and CD117 antibodies detected MC accumulation in the cortex and hippocampus from human and murine AD brains. Using MC-deficient KitW-sh/W-sh mice and over-the-counter (OTC) MC inhibitor ketotifen, we demonstrated that the absence or pharmacological inhibition of MCs reduced Aβ deposition and senile plaque formation in the hippocampus and cerebral cortex, and reduced the numbers of total Iba-1-positive microglia and CD68-positive phagocytic microglia in these regions in APPSWE-PS1∆e9+/– (APP-PS1) mice that develop cerebral amyloidosis. Brain tissue extract ELISA showed that the absence of MCs reduced the production of pathological Aβ species (Aβ1-40 and Aβ1-42). Adoptive transfer of in vitro-prepared MCs into KitW-sh/W-shAPP-PS1- recipient mice restored cortical and hippocampal Aβ deposition, microglia infiltration and activation, and AD brain cortex Aβ1-40 and Aβ1-42 contents. A preliminary water T-maze behavior test suggested that MC depletion improved cognitive decline in APP-PS1 mice. We hypothesize that MCs play a pathogenic role in AD by releasing pro-inflammatory cytokines and proteases, and MC inhibition with the anti-allergy drugs may become a novel therapy of human AD. We propose three aims to examine whether MC depletion or inhibition protects mice from Alzheimer’s disease; to examine whether genetic deficiency of FcεR1 or anti-IgE antibody therapy protects mice from Alzheimer’s disease and, to establish the mechanistic link between mast cell activation and mouse Alzheimer’s disease.

最近的研究表明，肥大细胞 (MC) 在过敏反应中也发挥着重要作用。通过释放炎症细胞因子、趋化因子和 MC-对其他炎症性疾病至关重要 MCs 脱颗粒后的特定蛋白酶食糜酶和类胰蛋白酶可防止或失活。减缓疾病进展。阿尔茨海默病（AD）是痴呆症和残疾的最常见原因。它是美国第六大死因，仅影响超过 500 万美国人，根据阿尔茨海默病协会的说法，AD 的一项明确诊断是基于是否存在 AD。神经毒性 β-淀粉样蛋白 (Aβ) 在人类 AD 大脑中的细胞外沉积有所增加。蛋白酶表达、神经元死亡和突触丢失、血脑屏障（BBB）泄漏以及激活小胶质细胞、星形胶质细胞和 T 细胞等炎症细胞也存在于人类 AD 大脑中，主要存在于大脑中。海马体、大脑皮层和丘脑，但研究尚未测试这些细胞是否参与直接参与发病机制或仅作为我们的初步数据的另一个炎症标志。证明 MC 激活剂 IgE 和 MC 颗粒含量类胰蛋白酶和组胺的血浆水平在早期 AD 患者中升高，表明全身 MC 激活增强。 CD117 抗体检测到人类和小鼠 AD 皮质和海马中 MC 的积累使用 MC 缺陷的 KitW-sh/W-sh 小鼠和非处方 (OTC) MC 抑制剂酮替芬，我们证明 MC 的缺失或药物抑制可减少 Aβ 沉积和老年斑海马体和大脑皮层的形成，并减少 Iba-1 阳性小胶质细胞的总数和 CD68 阳性吞噬小胶质细胞在 APPSWE-PS1Δe9+/– (APP-PS1) 小鼠的这些区域中发育脑淀粉样变性的脑组织提取物 ELISA 显示，MCs 的缺失减少了 β-淀粉样变性的产生。病理性 Aβ 物种（Aβ1-40 和 Aβ1-42）将体外制备的 MC 过继转移至 KitW-sh/W-shAPP-PS1- 中。受体小鼠恢复皮质和海马 Aβ 沉积、小胶质细胞浸润和激活以及 AD 大脑皮层 Aβ1-40 和 Aβ1-42 含量初步水 T 迷宫行为测试表明 MC 耗竭。改善 APP-PS1 小鼠的认知能力下降释放促炎细胞因子和蛋白酶，抗过敏药物对 MC 的抑制可能会变得我们提出了三个目标来检验 MC 消耗或抑制是否具有保护作用。患有阿尔茨海默病的小鼠；检查 FcεR1 或抗 IgE 抗体治疗是否存在遗传缺陷保护小鼠免受阿尔茨海默病的侵害，并建立肥大细胞激活和小鼠阿尔茨海默病。