Role of Complement Receptor Activation in a Mixed Dementia Model

阿尔茨海默病(AD)和脑血管疾病(CBVD)并存，定义混合性痴呆 (MXD)存在于许多(如果不是大多数)AD患者中。高血压是主要的危险因素。 与脑白质(WM)损害相关，导致CBVD，导致小血管疾病(SVD) MXD的特点，但MXD模型的缺乏限制了对机制的理解和进展 治疗这种常见病的疗法。例如，用于清除淀粉样蛋白(Abeta)的药物可能会加剧 CBVD，并且未能针对AD和CBVD之间知之甚少的协同作用。我们的新型大鼠MXD模型展示了 血管和AD并存的病理(AD转基因)，高血压和SVD加重AD- 相关的异常神经炎、线粒体功能障碍和肌萎缩症(Denver等人)。2019年)。自.以来 最近的临床数据显示，WM的损害与肌萎缩侧索硬化症的传播有关，而不是Abeta(Kapasi et (等，2022)，这进一步验证了我们的模型。用tau纤维种植MXD大鼠的进一步新数据 在人类AD/MXD中可见tau扩散。该模型是通过将TG AD培育成SHR-卒中而产生的 研究背景SHRSP大鼠模型是目前研究最广泛的血管认知障碍和SVD模型， 显示出受损的神经血管单位。与老鼠不同，老鼠表达所有6种tau亚型，而且 比小鼠更适合进行复杂的成像和行为测试，以及评估流体生物标记物。中环 假设：a)补体因素是协同驱动MXD和AD的主要成分，以及b)存在 是tau致病机制和补体激活之间的正反馈循环，从而拮抗 与基于结构的抑制剂(目标2)或补体级联(目标3)的tau聚集将不成比例 减少高血压MXD模型中的WM损伤、伸展障碍和执行功能缺陷。目标1将确定 关键的MRI和激光捕获的病理RNA表达谱。1A检查纵向变化 可翻译的MRI成像测量(包括SVD、脱髓鞘、萎缩和血脑屏障渗漏)，区分 来自AD的MXD。在1B中，我们在IHC引导下进行激光捕获显微镜解剖(LCM)和RNA序列 这些具有MRI特征的大鼠分布在三个区域，表现为肌张力增加(海马区)， 脱髓鞘/WMH(背外侧/前额叶皮质)和SVD(丘脑/壳核)以定义MXD特异性、病变- 相关的路径。目标2和3调查阿尔茨海默病和高血压如何相互作用来影响积极反馈 补体和互补性之间的循环。Aim 2使用了一种基于结构的tau聚集抑制剂，我们 以tau小鼠模型为特征。Aim 3使用了一种最先进的口服生物利用度和脑透性小 分子抑制物(见字母)，以研究C5aR激活可以驱动紧张症的原因作用，BBB 故障和WM丢失。结果。结果集中在血脑屏障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。脑脊液/血浆生物标志物 评估：特定验证的AD生物标记物(ptau、NFL、Abeta40/42)和与脑相关的标记物 炎症(GFAP、AQP4(星形细胞端足蛋白))或WMH(补体因子C3b和BB)和 神经保护(BDNF)，以确定它们在tau-补体C5a反馈环中的作用。解读：进步 可能包括高血压增强型直肠反流和/或C5aR和直肠反流增强型血脑屏障的演示 崩溃和一种或多种有效的新疗法。或者，tau聚合体抑制剂可能不会阻碍 血脑屏障和炎症发病机制，表明tau-炎症-血脑屏障环起了次要作用，并主张 综合疗法。哪些上游C3相关炎症成分或下游C5b成分被抑制 通过C5aR抑制剂将对MXD中tau-补体反馈相互作用提供重要的洞察力。RNASeq IS 可能填补在理解推动AD病理转化的SVD机制方面的主要知识空白 到认知功能衰退的开始。我们的建议得到了一个在中风方面拥有专业知识的多学科团队的支持， MRI成像、LCM/RNAseq、补体激活、CBVD/AD神经病理学和执行功能障碍。

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.