Role of Mast cells in Alzheimer's Disease

肥大细胞在阿尔茨海默病中的作用

• 批准号: 10565862
• 负责人: Peter Libby
• 金额: $ 61.79万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 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/10565862
• 关键词: Adoptive Transfer; Affect; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' 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; Cd68; 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; 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; 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; 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; pharmacologic; prevent; reconstitution; therapeutic evaluation

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.

肥大细胞在变态反应中起重要作用。最近的研究表明，MC也是 通过释放炎性细胞因子、趋化因子和MC-1， 脱粒后的特异性蛋白酶糜蛋白酶和类胰蛋白酶。MC的药理学失活防止或 减缓疾病进展。阿尔茨海默病（AD）是老年痴呆症和残疾的最常见原因， 老人它是美国第六大死亡原因，仅影响了500多万美国人， 根据阿尔茨海默氏症协会。AD的一种确定性诊断是基于以下情况的存在： 神经毒性β-淀粉样蛋白（Aβ）细胞外沉积到老年斑中。人类AD患者的大脑 蛋白酶表达、神经元死亡和突触丧失、血脑屏障（BBB）渗漏和 炎性细胞如小胶质细胞、星形胶质细胞和T细胞。MC也存在于人类AD大脑中，主要存在于 海马体，大脑皮层和丘脑，但研究还没有测试这些细胞是否参与 直接参与发病机制或仅作为另一种炎症标志。我们的初步数据 表明血浆MC激活剂IgE和MC颗粒含量 在早期AD患者中升高，表明增强的全身MC活化。抗类胰蛋白酶和 CD 117抗体检测到MC积累在大脑皮层和海马从人类和小鼠AD 大脑使用MC缺陷型KitW-sh/W-sh小鼠和非处方（OTC）MC抑制剂酮替芬，我们 表明MCs的缺乏或药理学抑制可减少Aβ沉积和老年斑， 海马和大脑皮质中的Iba-1阳性小胶质细胞总数减少 和CD 68阳性吞噬小胶质细胞在这些区域中的APPSWE-PS1 β 9 +/-（APP-PS1）小鼠， 脑淀粉样变性脑组织提取物ELISA显示，MCs的缺乏减少了 病理性Aβ种类（Aβ1-40和Aβ1-42）。将体外制备的MC连续转移到KitW-sh/W-shAPP-PS1中。 受体小鼠恢复了皮质和海马Aβ沉积、小胶质细胞浸润和活化， 脑皮质Aβ1-40和Aβ1-42含量。初步的水T-迷宫行为测试表明， 改善APP-PS1小鼠的认知能力下降。我们假设MC在AD中起致病作用， 释放促炎细胞因子和蛋白酶，抗过敏药物抑制MC可能成为 一种治疗人类AD的新方法。我们提出了三个目的，以检查是否MC耗竭或抑制保护 从阿尔茨海默病小鼠;检查是否遗传缺陷的FcεR1或抗IgE抗体治疗 保护小鼠免受阿尔茨海默氏病，并建立肥大细胞活化和 小鼠阿尔茨海默病。