Neuroinflammation and Neurodegeneration in a Transgenic Alzheimer Rat with Vascular Disease

患有血管疾病的转基因阿尔茨海默大鼠的神经炎症和神经变性

• 批准号: 10478805
• 负责人: SALLY ANN FRAUTSCHY
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10478805
• 关键词: APP-PS1; Address; Adverse effects; Age; Age-Months; Age-associated memory impairment; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; Amyloid; Amyloid beta-Protein; Amyloid deposition; Animal Model; Animals; Anti-Inflammatory Agents; Antibodies; Attenuated; Autopsy; Autoradiography; Binding; Biological Markers; Blood; Blood Vessels; Brain; Cardiovascular Diseases; Cell Adhesion; Cell Adhesion Molecules; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrum; Chronic; Clinical; Clinical Trials; Cognition; Cognitive; Cognitive deficits; Combined Modality Therapy; Curcumin; Data; Dementia; Deposition; Development; Diagnostic tests; Diffuse; Disease; Endothelial Cells; Endothelium; Evans blue stain; Exhibits; Extravasation; Female; Finding by Cause; Gender; Gliosis; Glucose Transporter; Histology; Human; Hypertension; Image; Immunization; Immunoglobulin G; Inbred SHR Rats; Inflammation; Injections; Insulin Resistance; Intervention; Knowledge; Label; Link; Literature; Long-Term Effects; Magnetic Resonance Imaging; Metabolic syndrome; Methodology; Methods; Modeling; Mus; Mutation; Nerve Degeneration; Neurofibrillary Tangles; Onset of illness; Outcome; Outcome Study; Passive Immunization; Pathogenesis; Pathology; Patients; Penetration; Peripheral; Phenotype; Plasma; Population; Populations at Risk; Prevalence; Property; Proteins; Rattus; Risk; Risk Factors; Role; Sampling; Senile Plaques; Stroke; Supplementation; Surrogate Markers; Synapses; T cell response; Tauopathies; Testing; Therapeutic; Therapeutic Intervention; Transgenes; Transgenic Organisms; Treatment Efficacy; Vaccines; Vascular Dementia; Vascular Diseases; Veterans; abeta deposition; age related; antagonist; beta-site APP cleaving enzyme 1; blood-brain barrier disruption; blood-brain barrier permeabilization; cerebral microbleeds; cerebrovascular; cerebrovascular amyloid; cerebrovascular pathology; comparative efficacy; dementia risk; diagnostic biomarker; dietary; hypertensive; male; military veteran; mixed dementia; molecular marker; mouse model; neuroimaging; neuroinflammation; neuron loss; neurovascular unit; novel; offspring; particle; prevent; relating to nervous system; response; sedentary lifestyle; serial imaging; sex; success; synergism; tau Proteins; tau aggregation; vascular inflammation; vasogenic edema; western diet; white matter

Vascular dementia (VaD) is often caused by small vessel arteriosclerotic disease, resulting in ischemic damage to white matter and associated neurodegeneration. Autopsy studies indicate that such changes contribute to the roughly one-third of dementia cases attributed to mixed pathology (MxD), with features of both Alzheimer's disease (AD) and VaD. MxD is particularly prevalent among older Veterans, who have increased risk factors such as metabolic syndrome and cardiovascular disease. However, current clinical trials with AD therapeutics frequently exclude patients with MxD. The interactions of vascular and AD pathology remain elusive, in part due to the dearth of animal models that recapitulate MxD symptomology and pathology. Our project addresses this hurdle, establishing a novel rat model of MxD to elucidate mechanisms associated with vascular complications in AD. We examine the impact of promising therapeutics to prevent AD in the MxD model, focusing on amyloid vaccines, to facilitate the development of combination therapies that can minimize adverse effects of vaccine in MxD patients, such as vasogenic edema and microbleeds. Although asymptomatic in patients with pure AD, the impact on AD patients with VaD is unknown. This proposal will assess: a) if VaD exacerbates AD-associated Aβ and/or tau pathology; b) differences in peripheral and central inflammation in VaD, AD, and MxD relative to cognitive and/or neurodegenerative parameters; c) whether plasma endothelial microparticles differentiate VaD, AD, and MxD; and d) the effects of known modifiers of AD pathology on MxD. This proposal uses an APP/PS1 transgenic rat model of AD, which develops age-related cognitive deficits, Aβ/tau deposition, and gliosis. In Aim 1, we examine the impact of this FAD transgene in spontaneously hypertensive stroke-prone (SHR-SP) rats, which exhibits age-related vascular and white matter pathology, neuron loss and progressive cognitive deficits. This MxD model (SHR-FAD) is compared with FAD positive controls and nonTg rats [SHR-SP versus the control strain WKY] for differences in cognition; peripheral and central inflammation, vascular and parenchymal Aβ, and synaptic loss; and other AD- and VaD- associated pathologies. Plasma and CSF biomarkers corresponding to specific disease pathologies will be identified. Aim 2 investigates interventions that promote amyloid clearance: passive immunization with an anti- Aβ antibody and curcumin, a pleiotropic Aβ-binding molecule, to determine their effects on vascular Aβ deposition and cerebrovascular disease in the SHR-FAD model of MxD. We hypothesize that VaD exacerbates neuroinflammation, synaptic loss and tau accumulation, but reduces neuritic plaques, increasing cerebrovascular amyloid deposition. Increased cerebral penetration of the peripheral anti-Aβ antibodies and increased plasma levels of cerebrovascular microparticles and cellular adhesion molecules may parallel disruption of the blood brain barrier. Completion of these aims is likely to provide knowledge important for AD trials in patients who also have VaD.

血管性痴呆（VAD）通常是由小血管动脉粥样硬化疾病引起的，导致缺血性 对白质和相关神经变性的损害。尸检研究表明这种变化 造成混合病理（MXD）的大约三分之一的痴呆病例，两者的特征 阿尔茨海默氏病（AD）和VAD。 MXD在增加的老兵中尤为普遍 危险因素，例如代谢综合征和心血管疾病。但是，当前的AD临床试验 治疗经常排除MXD患者。血管和AD病理的相互作用仍然存在 难以捉摸，部分原因是概括了MXD症状和病理学的动物模型死亡。我们的 项目解决了这一障碍，建立了新型的MXD大鼠模型，以阐明与 AD的血管并发症。我们研究了有前途的疗法预防MXD中AD的影响 模型，专注于淀粉样疫苗，以促进可以最小化的组合疗法的发展 疫苗在MXD患者中的不良影响，例如血管性水肿和微血管。虽然 无症状的纯AD患者，对VAD AD患者的影响尚不清楚。该提议将 评估：a）如果VAD加剧了与AD相关的Aβ和/或TAU病理； b）外围和中央的差异 VAD，AD和MXD的炎症相对于认知和/或神经退行性参数； c）是否 血浆内皮微粒区分VAD，AD和MXD； d）已知的AD修饰符的影响 MXD的病理学。该建议使用AP/PS1转基因大鼠AD的模型，该模型发展为与年龄有关的 认知缺陷，Aβ/TAU沉积和神经胶质病。在AIM 1中，我们研究了这种时尚变换的影响 赞助的高血压中风（SHR-SP）大鼠，表现出与年龄有关的血管和白质 病理学，神经元丧失和进行性认知缺陷。将此MXD模型（SHR-FAD）与FAD进行比较 认知差异的阳性对照和非对照菌株的阳性大鼠[SHR-SP与对照菌株WKY]； 外围和中央感染，血管和副群Aβ以及突触损失；以及其他广告和vad- 相关的病理。与特定疾病病理相对应的血浆和CSF生物标志物将是 确定。 AIM 2调查促进淀粉样蛋白清除率的干预措施：抗药性免疫 Aβ抗体和姜黄素是多效性Aβ结合分子，以确定它们对血管Aβ的影响 MXD的SHR-FAD模型中的沉积和脑血管疾病。我们假设VAD加剧了 神经炎症，突触损失和TAU积累，但减少了神经质斑块，增加 脑血管淀粉样蛋白沉积。外周抗Aβ抗体的大脑渗透增加和 脑血管微粒和细胞粘附分子的血浆水平增加可能平行 血脑屏障的破坏。这些目标的完成可能会为广告提供重要的知识 也有VAD的患者试验。

项目成果

A sensitive LC-MS assay using derivatization with boron trifluoride to quantify curcuminoids in biological samples.

• DOI: 10.1016/j.ab.2020.113636
• 发表时间: 2020-05-01
• 期刊: Analytical biochemistry
• 影响因子: 2.9

Neuronal pentraxin 1: A synaptic-derived plasma biomarker in Alzheimer's disease.

• DOI: 10.1016/j.nbd.2018.02.014
• 发表时间: 2018-06
• 期刊: Neurobiology of disease
• 影响因子: 6.1
• 作者: Ma QL;Teng E;Zuo X;Jones M;Teter B;Zhao EY;Zhu C;Bilousova T;Gylys KH;Apostolova LG;LaDu MJ;Hossain MA;Frautschy SA;Cole GM
• 通讯作者: Cole GM

Modeling Mixed Vascular and Alzheimer's Dementia Using Focal Subcortical Ischemic Stroke in Human ApoE4-TR:5XFAD Transgenic Mice.

• DOI: 10.1007/s12975-020-00786-0
• 发表时间: 2020-10
• 期刊: TRANSLATIONAL STROKE RESEARCH
• 影响因子: 6.9
• 作者: Hayden, Eric Y.;Huang, Julia M.;Charreton, Malena;Nunez, Stefanie M.;Putman, Jennifer N.;Teter, Bruce;Lee, Jason T.;Welch, Andrew;Frautschy, Sally;Cole, Gregory;Teng, Edmond;Hinman, Jason D.
• 通讯作者: Hinman, Jason D.

CR3 ruffles FcγR's claim over phagocytic cups.

• DOI: 10.1016/j.jbc.2021.100801
• 发表时间: 2021-01
• 期刊: The Journal of biological chemistry
• 作者: Frautschy SA

Curcumin Ameliorates Neuroinflammation, Neurodegeneration, and Memory Deficits in p25 Transgenic Mouse Model that Bears Hallmarks of Alzheimer's Disease.

• DOI: 10.3233/jad-170093
• 发表时间: 2017
• 期刊: Journal of Alzheimer's disease : JAD
• 作者: Sundaram JR;Poore CP;Sulaimee NHB;Pareek T;Cheong WF;Wenk MR;Pant HC;Frautschy SA;Low CM;Kesavapany S
• 通讯作者: Kesavapany S