Role of Complement Receptor Activation in a Mixed Dementia Model

补体受体激活在混合痴呆模型中的作用

• 批准号: 10585080
• 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: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585080
• 关键词: Acceleration; Address; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Animal Model; Animal Testing; Area; Astrocytes; Atrophic; Attenuated; Automobile Driving; Behavior; Biochemical; Biological Availability; Biological Markers; Blocking Antibodies; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain-Derived Neurotrophic Factor; Breeding; Budgets; Caregivers; Cerebral small vessel disease; Cerebrovascular Disorders; Characteristics; Chronic; Clinical; Clinical Data; Combined Modality Therapy; Complement; Complement 3 Convertase; Complement 3b; Complement 5a; Complement Activation; Complement Receptor; Complex; Data; Dementia; Demyelinations; Development; Diagnosis; Disease; Dissection; Drug Design; Encephalitis; Euthanasia; Executive Dysfunction; Exhibits; Extravasation; Feedback; Female; Funding; Genes; Genetic Transcription; Glial Fibrillary Acidic Protein; Gliosis; Health; Hemorrhage; Hippocampus; Histologic; Histology; Human; Hypertension; Hypoxia; Image; Impaired cognition; Inflammation; Inflammatory; K-18 conjugate; Knowledge; Label; Lasers; Lesion; Letters; Liquid substance; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Mediating; Medicare; Methods; Microglia; Microscopy; Microvascular Dysfunction; Minor; Modeling; Mus; Nerve Degeneration; Neurons; Oral; Oral Administration; Outcome; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Plasma; Play; Prefrontal Cortex; Process; Protein Isoforms; Proteins; Randomized; Rat Transgene; Rattus; Receptor Activation; Resistance; Risk; Risk Factors; Role; Scanning; Serial Magnetic Resonance Imaging; Serum; Signal Transduction; Solid; Stroke; Structure; Study models; Subarachnoid Hemorrhage; Tauopathies; Testing; Thalamic structure; Therapeutic; Time; Transgenic Organisms; Treatment Efficacy; Validation; Vascular Cognitive Impairment; Vascular Dementia; Veterans; aged; antagonist; behavior test; biomarker validation; complement C5b; complement pathway; design; differential expression; drug development; early onset; familial Alzheimer disease; global health; hypertensive; improved; inflammatory marker; inhibitor; insight; interest; male; mitochondrial dysfunction; mixed dementia; monomer; mouse model; multidisciplinary; myelination; neuroimaging; neuroinflammation; neuron loss; neuropathology; neuroprotection; neurotoxic; neurovascular unit; normotensive; novel; novel therapeutics; pharmacokinetics and pharmacodynamics; putamen; response; sex; small molecule inhibitor; synergism; tau Proteins; tau aggregation; transcriptome sequencing; white matter; white matter damage

The coexistence of Alzheimer (AD) and cerebrovascular disease (CBVD), which defines Mixed Dementia (MxD) is present in many, if not most, of those diagnosed with AD. Hypertension is the major risk factor contributing to CBVD, driving small vessel disease (SVD), associated with white matter (WM) lesions characteristic of MxD, but the paucity of MxD models limits progress to understand mechanisms and advance therapeutics for this common disease. For example, drugs developed to clear amyloid (Abeta) may exacerbate CBVD, and fail to target poorly understood synergism between AD and CBVD. Our novel rat MxD model exhibits coexisting vascular and AD pathologies (AD transgenic), whereby hypertension and SVD exacerbate AD- associated aberrant neuroinflammation, mitochondrial dysfunction and tauopathy (Denver et al. 2019). Since recent clinical data, showing that WM damage is associated with the spread of tauopathy, not Abeta (Kapasi et al., 2022), this further validates our model. Further new data on seeding of MxD rats with tau fibrils, recapitulates tau spreading seen in human AD/MxD. The model was produced by breeding the Tg AD into a SHR-Stroke prone (SHRSP) rat background, the most widely studied model for vascular cognitive impairment and SVD, which exhibits a compromised neurovascular unit. Unlike mice, rats express all 6 tau isoforms and are more suitable than mice for complex imaging and behavioral testing, and assessing fluid biomarkers. The central hypotheses are: a) Complement factors are major components synergistically driving MxD and AD, and b) there is a positive feedback loop between tau pathogenesis and complement activation such that antagonizing either tau aggregation with structure-based inhibitors (Aim 2) or the complement cascade (Aim 3) will disproportionately reduce WM damage, tauopathy and executive function deficits in the hypertensive MxD model. Aim 1 will identify key MRI and laser captured pathology RNA expression profiles. 1A examines longitudinal changes of translatable MRI imaging measures (including SVD, demyelination, atrophy, and BBB leakage) that distinguish MxD from AD. In 1B, we perform IHC-guided laser capture microscopy dissection (LCM) and RNA seq in these MRI-characterized rats in 3 regions representing increased tauopathy (hippocampus), demyelination/WMH (dorsolateral/prefrontal cortex) and SVD (thalamus/putamen) to define MxD-specific, lesion- related pathways. Aims 2 and 3 investigate how AD and hypertension interact to influence a positive feedback loop between complement and tauopathy. Aim 2 uses a structure-based tau aggregation inhibitor that we characterized in tau mouse models. Aim 3 uses a state-of-the-art orally bioavailable and brain penetrant small molecule inhibitor (see letters), to investigate the causal role of C5aR activation that can drive tauopathy, BBB breakdown and WM loss. Outcomes. Outcomes focus on regional biochemical and histological changes in BBB, myelination, neurodegeneration, neuroinflammation and executive function deficits. CSF/plasma biomarkers are assessed: specifically validated AD biomarkers (ptau, NFL, Abeta40/42) and those associated with brain inflammation (GFAP, AQP4 (astrocytic endfoot protein)) or WMH (complement factors C3b, and Bb) and neuroprotection (BDNF) to identify their role in the tau-complement C5a feedback loop. Interpretation: Advances may include demonstration of hypertension-enhanced tauopathy and/or C5aR and tauopathy-enhanced BBB breakdown and one or more effective new treatments. Alternatively, tau aggregate inhibitors may not impede BBB and inflammatory pathogenesis, suggesting a minor role for the tau-inflammation-BBB loop and arguing for combination therapies. Which upstream C3-related inflammatory or downstream C5b components are inhibited by C5aR inhibitors will provide important insight into tau-complement feedback interactions in MxD. RNAseq is likely to fill major knowledge gaps in understanding mechanisms of SVD that drive conversion from AD pathology to onset of cognitive decline. Our proposal is strengthened by a multidisciplinary team with expertise in stroke, MRI imaging, LCM /RNAseq, complement activation, CBVD/AD neuropathology, and executive dysfunction.

阿尔茨海默病（AD）和脑血管病（CBVD）共存，定义为混合性痴呆 (MxD)存在于许多（如果不是大多数）被诊断患有AD的人中。高血压是主要的危险因素 导致CBVD，驱动小血管疾病（SVD），与白色（WM）病变相关 MxD的特征，但MxD模型的缺乏限制了理解机制和推进的进展 这种常见疾病的治疗方法。例如，开发用于清除淀粉样蛋白（Abeta）的药物可能会加剧 CBVD之间的协同作用，并且未能靶向AD和CBVD之间的尚不清楚的协同作用。我们的新型大鼠MxD模型显示， 共存的血管和AD病理（AD转基因），由此高血压和SVD加重AD- 相关的异常神经炎症、线粒体功能障碍和tau蛋白病（Denver et al. 2019）。以来 最近的临床数据显示，WM损伤与tau蛋白病的传播有关，而与Abeta无关（Kapasi et 例如，2022年，这进一步验证了我们的模型。关于用tau原纤维接种MxD大鼠的进一步新数据， 在人类AD/MxD中观察到的tau扩散。该模型是通过将Tg AD繁殖成SHR中风模型而产生的。 俯卧（SHRSP）大鼠背景，血管性认知障碍和SVD的最广泛研究模型， 显示出神经血管受损与小鼠不同，大鼠表达所有6种tau亚型， 比小鼠更适合于复杂的成像和行为测试，以及评估流体生物标志物。中央 假设是：a）补体因子是协同驱动MxD和AD的主要成分，和B）存在 是tau发病机制和补体激活之间的正反馈环， 基于结构的抑制剂（Aim 2）或补体级联（Aim 3）的tau聚集将不成比例地 减少高血压MxD模型中的WM损伤、tau蛋白病和执行功能缺陷。目标1将确定 关键的MRI和激光捕获病理RNA表达谱。图1A考察了 可翻译的MRI成像测量（包括SVD、脱髓鞘、萎缩和BBB渗漏）， AD的MXD在图1B中，我们进行了IHC引导的激光捕获显微镜解剖（LCM）和RNA测序。 这些MRI表征的大鼠在代表增加的tau蛋白病（海马）的3个区域中， 脱髓鞘/WMH（背外侧/前额皮质）和SVD（丘脑/壳核），以定义MxD特异性病变- 相关路径目的2和3研究AD和高血压如何相互作用以影响正反馈 补体和tau蛋白病之间的循环。AIM 2使用了一种基于结构的tau蛋白聚集抑制剂， 在tau小鼠模型中表征。AIM 3使用最先进的口服生物可利用性和脑渗透剂小 分子抑制剂（见字母），以研究C5 aR激活的因果作用，可以驱动tau蛋白病，血脑屏障 故障和WM损失。结果。结果集中在BBB的局部生化和组织学变化， 髓鞘形成、神经变性、神经炎症和执行功能缺陷。CSF/血浆生物标志物是 评估：专门验证的AD生物标志物（ptau，NFL，Abeta 40/42）和与脑相关的生物标志物 炎症（GFAP、AQP 4（星形胶质细胞终足蛋白））或WMH（补体因子C3 b和Bb），以及 神经保护（BDNF），以确定其在tau-补体C5 a反馈回路中的作用。解释：预付款 可能包括高血压增强的tau蛋白病和/或C5 aR和tau蛋白病增强的BBB的证明 一种或多种有效的治疗方法。或者，tau聚集体抑制剂可能不会阻碍 BBB和炎症发病机制，表明tau-炎症-BBB环的作用较小，并认为 联合治疗哪些上游C3相关炎症或下游C5 b组分受到抑制 通过C5 aR抑制剂将提供重要的洞察tau-补体反馈相互作用在MxD。RNAseq是 可能填补理解SVD机制的主要知识空白，该机制驱动AD病理学的转化 认知能力下降我们的建议得到了一个具有中风专业知识的多学科团队的加强， MRI成像、LCM /RNAseq、补体激活、CBVD/AD神经病理学和执行功能障碍。