The protein tyrosine kinase SYK drives innate immune responses against Alzheimer's Disease

蛋白质酪氨酸激酶 SYK 驱动针对阿尔茨海默病的先天免疫反应

• 批准号: 10674689
• 负责人: MARCO COLONNA
• 金额: $ 59.72万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10674689
• 关键词: Abeta clearance; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Antibodies; Apolipoprotein E; Attenuated; Autophagocytosis; Behavior; Biochemistry; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; C Type Lectin Receptors; Candidate Disease Gene; Cerebral Amyloid Angiopathy; Cerebrovascular system; Collaborations; Comprehension; Cytoplasm; DNA; DNA Sequence Alteration; Data; Defect; Dementia; Disease Progression; Disease associated microglia; Endothelial Cells; Extracellular Matrix; FRAP1 gene; Genes; Genetic; Genetic study; Hemorrhage; Human; Hypercapnia; ITAM; Impairment; Individual; Innate Immune Response; Intervention; Laboratories; Late Onset Alzheimer Disease; Leptomeninges; Ligands; Lipids; Lymphatic; Macrophage; Maintenance; Mediator; Membrane; Memory impairment; Metabolic; Microglia; Modeling; Monoclonal Antibodies; Mus; Natural Immunity; Nerve Degeneration; Neurites; Neurofibrillary Tangles; PIK3CG gene; Pathologic; Pathology; Pathway interactions; Phenotype; Play; Production; Proliferating; Protein Tyrosine Kinase; Regulation; Role; SYK gene; Senile Plaques; Signal Transduction; Surface; TREM2 gene; TYROBP gene; Tauopathies; Testing; Tyrosine Phosphorylation; Variant; abeta accumulation; aged; amyloid pathology; apolipoprotein E-4; beta amyloid pathology; brain tissue; experimental study; extracellular; genetic risk factor; high risk; lipid metabolism; metabolomics; mouse model; neuroimmunology; neuron loss; new therapeutic target; novel therapeutics; photoacoustic imaging; preservation; receptor; receptor expression; recruit; response; tau Proteins; tau aggregation; tau-1; transmission process; two photon microscopy; vasoconstriction; vasomotion

PROJECT SUMMARY Alzheimer's disease (AD) is the most common cause of dementia. Pathological hallmarks of AD are extracellular amyloid-β (Aβ) plaques, intraneuronal neurofibrillary tangles of tau aggregates, and neuronal death. There are no approved therapies that can halt or reverse AD progression. The greatest risk factors of AD include age and genetics. Among genetic risk factors, a DNA variant of the receptor TREM2, TREM2R47H, impairs the ability of microglia to restrict spreading of Aβ plaques. TREM2 transmits intracellular signals through the adaptor DAP12 that recruits the protein tyrosine kinase SYK, which promotes tyrosine phosphorylation of multiple downstream mediators. Highlighting the importance of SYK signaling in AD, microglia associated with Aβ plaques upregulate the expression of CD300LB, CD200R4, and CLEC7A, all of which activate SYK either through DAP12 or by directly recruiting SYK. However, not much is known about SYK signaling in AD. Project 4 will explore this black box, elucidating the impact of SYK on microglia and parenchymal border macrophage (PBM) function in AD and cerebral amyloid angiopathy (CAA) models. Aim 1 will test the hypothesis that SYK is a major driver of microglia responses to Aβ and tau. Our preliminary data indicate that SYK deficiency impairs microglia clustering around Aβ plaques, which facilitates Aβ accumulation, neurite dystrophy and memory deficits. Moreover, SYK-deficient microglia show evidence of increased autophagy and lipid dysmetabolism. However, microglia proliferation and ApoE production are maintained through a SYK-independent pathway. Based on these premises, we will test the following hypotheses: a) microglia require SYK to control both Aβ and tau pathology; b) SYK-deficient microglia are impaired because of a major metabolic defect involving the mTOR pathway, autophagy and lipid metabolism; c) ApoE production and proliferation of SYK-deficient microglia are sustained by a DAP10 pathway associated with TREM2. Aim 2 will test the hypothesis that SYK activation by anti-CLEC7A alleviates Aβ pathology. Our preliminary data demonstrate that engagement of CLEC7A rescues microglia activation in the TREM2R47H-5xFAD model, in which microglia are defective due to the TREM2 variant. CLEC7A is a C-type lectin receptor that directly recruits SYK and is expressed by microglia in mice with AD pathology. To test our hypothesis, we will determine whether systemic administration of an anti-CLEC7A antibody as a surrogate ligand ameliorates pathology and behavior in TREM2R47H-5xFAD mice. Aim 3 will test the hypothesis that PBMs require SYK to clear Aβ in CAA. Our preliminary data demonstrate that PBMs express SYK. PBMs have been shown to diminish the Aβ load in CAA independently of microglia. We will test our hypothesis in a model for CAA, 5xFAD- APOE4 mice, crossed with mice lacking SYK in PBMs. We will assess vascular amyloid pathology, vasomotion by photoacoustic imaging and 2P-microscopy, as well as microhemorrhages in collaboration with the Kipnis and Randolph labs. Through integration with projects 1, 2, 3 and Core B, Project 4 will provide deep comprehension of mechanisms underlying microglia and PBM responses in AD and CAA and unearth a novel therapeutic target.

项目摘要 阿尔茨海默病（AD）是痴呆症最常见的原因。AD的病理特征是细胞外 淀粉样蛋白-β（Aβ）斑块、tau聚集体的神经元内神经纤维缠结和神经元死亡。有 没有批准的治疗可以阻止或逆转AD进展。AD的最大风险因素包括年龄和 遗传学在遗传风险因素中，受体TREM 2的DNA变体TREM 2 R47 H损害了细胞的增殖能力。 小胶质细胞限制Aβ斑块的扩散。TREM 2通过衔接子DAP 12传递细胞内信号 它募集蛋白酪氨酸激酶SYK，促进多个下游酪氨酸磷酸化。 调解员强调SYK信号在AD中的重要性，与Aβ斑块相关的小胶质细胞上调 CD 300 LB、CD 200 R4和CLEC 7A的表达，所有这些都通过DAP 12或 直接招募SYK然而，对AD中的SYK信号传导知之甚少。Project 4将探索这片黑色 框，阐明了SYK对AD中小胶质细胞和实质边缘巨噬细胞（PBM）功能的影响， 脑淀粉样血管病（CAA）模型。目标1将测试SYK是小胶质细胞的主要驱动因素的假设 对Aβ和tau的反应。我们的初步数据表明SYK缺乏会损害周围小胶质细胞的聚集 Aβ斑块，其促进Aβ积聚、神经突营养不良和记忆缺陷。此外，SYK缺陷 小胶质细胞显示出增加的自噬和脂质代谢障碍的证据。然而，小胶质细胞增殖和 ApoE的产生通过SYK非依赖性途径维持。基于这些前提，我们将测试 以下假设：a）小胶质细胞需要SYK来控制Aβ和tau病理; B）SYK缺陷 由于涉及mTOR途径、自噬和脂质代谢的主要代谢缺陷， c）SYK缺陷型小胶质细胞的ApoE产生和增殖由DAP 10途径维持 与TREM 2相关。目的2将检验抗CLEC 7A激活SYK使Aβ活化的假设 病理我们的初步数据表明，CLEC 7A的参与挽救了小胶质细胞在脑内的激活。 TREM 2 R47 H-5xFAD模型，其中小胶质细胞由于TREM 2变体而有缺陷。CLEC 7A是C型凝集素 在AD病理学小鼠中，SYK受体直接募集SYK并由小胶质细胞表达。来测试我们 假设，我们将确定是否全身施用抗CLEC 7A抗体作为替代配体 改善TREM 2 R47 H-5xFAD小鼠的病理学和行为。目标3将检验PBM需要 SYK清除CAA中的Aβ。我们的初步数据表明PBM表达SYK。PBM已被证明 减少CAA中的Aβ负荷，而不依赖于小胶质细胞。我们将在CAA模型中测试我们的假设，5xFAD- APOE 4小鼠，与PBM中缺乏SYK的小鼠杂交。我们将评估血管淀粉样病变，血管运动 通过光声成像和2 P显微镜，以及与Kipnis和 兰多夫实验室。通过与项目1、2、3和核心B的整合，项目4将提供深入的理解 研究AD和CAA中小胶质细胞和PBM反应的潜在机制，并发现新的治疗靶点。