Impact of atherosclerosis, metabolic syndrome, and STAT4-dependent immunity on Alzheimer's disease

动脉粥样硬化、代谢综合征和 STAT4 依赖性免疫对阿尔茨海默病的影响

• 批准号: 10284431
• 负责人: Elena V Galkina
• 金额: $ 40.28万
• 依托单位: EASTERN VIRGINIA MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10284431
• 关键词: Adoptive Transfer; Affect; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Atherosclerosis; Behavioral; Blood - brain barrier anatomy; Bone Marrow; Brain; Cardiovascular Diseases; Cells; Cholesterol; Chronic; Cognitive; Data; Dementia; Deposition; Development; Diet; Disease; Disease Progression; Elderly; Glutamate Receptor; Hippocampus (Brain); Homing; ITGAM gene; Immune; Immune response; Immunity; Impaired cognition; Impairment; Inflammation; Inflammatory; Interleukin-12; Investigation; Learning; Long-Term Depression; Long-Term Potentiation; Mediator of activation protein; Metabolic syndrome; Microglia; Modeling; Mus; Myeloid Cell Activation; Myeloid Cells; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroimmune; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Pathologic; Pathology; Pathway interactions; Pattern; Phagocytes; Phenotype; Play; Process; Production; Regulation; Role; STAT4 protein; Senile Plaques; Series; Shapes; Synapses; Synaptic Transmission; Synaptic plasticity; T-Lymphocyte; Testing; Therapeutic Intervention; Time; Transplantation; abeta deposition; atherogenesis; cognitive function; experimental study; extracellular; feeding; field study; frontal lobe; hyperphosphorylated tau; in vivo; long term memory; macrophage; member; memory consolidation; migration; mind control; neuroinflammation; neuron apoptosis; neuropathology; neurotransmission; neutrophil; novel; postsynaptic; presynaptic; promoter; trafficking; transmission process

Project Summary The increasing evidence of cardiovascular disease-related Alzheimer’s disease (AD) progression, and the closely associated role of inflammation in both diseases, opens new opportunities for understanding AD mechanisms and has the potential to unveil novel avenues for therapeutic intervention. While data indicate that atherosclerosis promotes AD development, the role of atherosclerosis-associated immunity in AD is not fully understood. Our recent studies have revealed the role of Signal Transducer and Activator of Transcription 4 (STAT4) in critical neutrophil (N and macrophage (M functions in the context of Type 2 diabetes (T2D)- associated atherosclerosis. These findings, in conjunction with the increasing understanding of N and M roles in AD, suggest a novel pathway to study neuroinflammation in AD development. In this application, we propose to investigate how STAT4 shapes N M and neuronal functions, and thus affects neuroinflammation, long-term activity-dependent synaptic plasticity, cognitive and behavioral functions in conditions of T2D-accelerated atherosclerosis. Aim 1 will determine how STAT4 regulates immune-associated neuroinflammation and AD-like neuropathology in T2D-associated atherosclerosis. As we show that a high cholesterol/ high carb diet (DDC) feeding supports T2D development and atherosclerosis in Ldlr-/- mice, we will use this model as a model of T2D-associated atherosclerosis. Stat4-/- Ldlr-/- and Ldlr-/- mice will be fed DDC diet for 16 wks and neuroimmune cell composition, amyloid plaques deposition, microglia activation and blood-brain barrier breakdown will be examined. To test a role of STAT4 in neurons, irradiated 16 wk DDC fed Stat4fl/fl LysMcre/creLdlr-/- and Ldlr-/- mice transplanted with Ldlr-/- bone marrow will be analyzed for neuroimmune composition, Aβ deposition, neuronal apoptosis, and activation of microglia. Finally, we will test to what extent myeloid cell specific- and neuron-specific STAT4 regulates myeloid cell homing into the AD-like brain in series of adoptive transfer experiments. In Aim 2, we will examine the extent to which STAT4 regulates synaptic plasticity in T2D-accelerated atherosclerosis. Specifically, we will test the effect of STAT4 deficiency on basal synaptic transmission, presynaptic transmitter release, long-term potentiation and long-term depression of synaptic strength at Schaffer collateral-CA1 synapses, which play a critical role in learning and long-term memory consolidation, and are impaired in AD. We will also examine whether STAT4 deficiency alters behavioral and cognitive functions in Stat4-/-Ldlr-/- and Ldlr-/- mice. Overall, this proposal will forge new lines of investigation by identifying STAT4-dependent mechanisms by which STAT4 impacts neuroinflammation and potential AD risk under conditions of T2D-associated atherosclerosis.

项目摘要 越来越多的证据表明，心血管疾病相关的阿尔茨海默病（AD）进展， 炎症在这两种疾病中的作用密切相关，为了解AD开辟了新的机会 机制，并有可能揭示新的治疗干预途径。虽然数据显示， 虽然动脉粥样硬化促进了AD的发展，但动脉粥样硬化相关免疫在AD中的作用尚不完全清楚， 明白我们最近的研究揭示了信号转导子和转录激活子4的作用 在2型糖尿病（T2 D）的背景下，关键中性粒细胞（NK细胞）和巨噬细胞（巨噬细胞）中的STAT 4的功能 相关动脉粥样硬化。这些发现，结合对N和M的作用的日益了解， 在AD中，提出了一种新途径来研究AD发展中神经炎症。 在这个应用中，我们提出研究STAT 4如何塑造神经元和神经元功能， 从而影响神经炎症、长期活动依赖性突触可塑性、认知和 2型糖尿病加速动脉粥样硬化的行为功能。目标1将确定STAT 4 调节T2 D相关的免疫相关神经炎症和AD样神经病理学 动脉粥样硬化正如我们所表明的，高胆固醇/高碳水化合物饮食（DDC）喂养支持T2 D发展 和动脉粥样硬化，我们将使用该模型作为T2 D相关动脉粥样硬化的模型。Stat4-/- Ldlr-/-和Ldlr-/-小鼠将被喂食DDC饮食16周，并将神经免疫细胞组成、神经胶质瘤淀粉样蛋白斑块 将检查沉积、小胶质细胞活化和血脑屏障破坏。为了测试STAT 4在以下中的作用： 神经元，辐照16周DDC喂养Stat 4fl/fl LysMcre/creLdlr-/-和Ldlr-/-小鼠，移植Ldlr-/-骨髓 将分析神经免疫组成、Aβ沉积、神经元凋亡和小胶质细胞活化。 最后，我们将测试髓样细胞特异性和神经元特异性STAT 4调节髓样细胞归巢的程度 在一系列的过继性转移实验中植入类似AD的大脑。在目标2中，我们将研究 STAT 4调节T2 D加速的动脉粥样硬化中的突触可塑性具体来说，我们将测试 STAT 4缺陷对基础突触传递、突触前递质释放、长时程增强和突触后突触后突触形成的影响 Schaffer侧支-CA 1突触的突触强度的长期抑制，其在 学习和长期记忆巩固，并在AD中受损。我们还将研究STAT 4是否 缺乏改变了Stat 4-/-Ldlr-/-和Ldlr-/-小鼠的行为和认知功能。总的来说，这项建议将 通过确定STAT 4影响的STAT 4依赖机制，建立新的研究路线 在T2 D相关动脉粥样硬化的条件下，神经炎症和潜在的AD风险。

项目成果

A Factor H-Fc fusion protein increases complement-mediated opsonophagocytosis and killing of community associated methicillin-resistant Staphylococcus aureus.

• DOI: 10.1371/journal.pone.0265774
• 发表时间: 2022
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Sage MAG;Cranmer KD;Semeraro ML;Ma S;Galkina EV;Tran Y;Wycoff KL;Sharp JA
• 通讯作者: Sharp JA

Role of neutrophils in type 2 diabetes and associated atherosclerosis.

• DOI: 10.1016/j.biocel.2021.106098
• 发表时间: 2021-12
• 期刊: The international journal of biochemistry & cell biology
• 作者: Keeter WC;Moriarty AK;Galkina EV
• 通讯作者: Galkina EV

Atherosclerosis and multi-organ-associated pathologies.

• DOI: 10.1007/s00281-022-00914-y
• 发表时间: 2022-05
• 期刊: SEMINARS IN IMMUNOPATHOLOGY
• 影响因子: 9
• 作者: Keeter, W. Coles;Ma, Shelby;Stahr, Natalie;Moriarty, Alina K.;Galkina, Elena V.
• 通讯作者: Galkina, Elena V.

Functional Role of B Cells in Atherosclerosis.

• DOI: 10.3390/cells10020270
• 发表时间: 2021-01-29
• 期刊: Cells
• 影响因子: 6
• 作者: Ma SD;Mussbacher M;Galkina EV
• 通讯作者: Galkina EV

ADAM17-dependent proteolysis of L-selectin promotes early clonal expansion of cytotoxic T cells.

L-选择素的 ADAM17 依赖性蛋白水解促进细胞毒性 T 细胞的早期克隆扩增。

• DOI: 10.1038/s41598-019-41811-z
• 发表时间: 2019
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Mohammed RN