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.

项目概要 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 β 淀粉样蛋白 (Aβ) 斑块、tau 蛋白聚集体的神经元内神经原纤维缠结和神经元死亡。有 没有批准的疗法可以阻止或逆转 AD 进展。 AD 的最大危险因素包括年龄和 遗传学。在遗传风险因素中，受体 TREM2 的 DNA 变体 TREM2R47H 会损害 小胶质细胞限制 Aβ 斑块的扩散。 TREM2通过适配器DAP12传输细胞内信号 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。与 Aβ 斑块相关的小胶质细胞上调，凸显了 SYK 信号传导在 AD 中的重要性 CD300LB、CD200R4 和 CLEC7A 的表达，所有这些都通过 DAP12 或通过 直接招募SYK。然而，人们对 AD 中的 SYK 信号传导知之甚少。项目4将探索这种黑色 框，阐明了 SYK 对 AD 和 AD 中小胶质细胞和实质边界巨噬细胞 (PBM) 功能的影响 脑淀粉样血管病（CAA）模型。目标 1 将检验 SYK 是小胶质细胞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 缺陷会损害周围小胶质细胞的聚集 Aβ 斑块，促进 Aβ 积累、神经突营养不良和记忆缺陷。此外，SYK 缺乏 小胶质细胞显示出自噬增加和脂质代谢异常的证据。然而，小胶质细胞增殖和 ApoE 的产生通过不依赖 SYK 的途径维持。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 病理学； b) SYK 缺陷 小胶质细胞因涉及 mTOR 通路、自噬和脂质的主要代谢缺陷而受损 代谢; c) SYK 缺陷型小胶质细胞的 ApoE 产生和增殖由 DAP10 途径维持 与 TREM2 相关。目标 2 将检验抗 CLEC7A 激活 SYK 减轻 Aβ 的假设 病理。我们的初步数据表明，CLEC7A 的参与可挽救小胶质细胞的激活 TREM2R47H-5xFAD 模型，其中小胶质细胞由于 TREM2 变异而有缺陷。 CLEC7A是一种C型凝集素 直接招募 SYK 的受体，并由患有 AD 病理的小鼠中的小胶质细胞表达。来测试我们的 假设，我们将确定是否全身施用抗 CLEC7A 抗体作为替代配体 改善 TREM2R47H-5xFAD 小鼠的病理和行为。目标 3 将检验 PBM 需要的假设 SYK 清除 CAA 中的 Aβ。我们的初步数据表明 PBM 表达 SYK。 PBM 已被证明可以 独立于小胶质细胞减少 CAA 中的 Aβ 负荷。我们将在 CAA、5xFAD 模型中检验我们的假设 - APOE4 小鼠与 PBM 中缺乏 SYK 的小鼠杂交。我们将评估血管淀粉样蛋白病理学、血管舒缩 通过光声成像和 2P 显微镜，以及与 Kipnis 和 伦道夫实验室。通过与项目 1、2、3 和核心 B 的集成，项目 4 将提供深入的理解 研究 AD 和 CAA 中小胶质细胞和 PBM 反应的机制，并发掘新的治疗靶点。