Hyaluronan and the microvascular and neuropathology of Alzheimer’s Disease

细胞外基质(ECM)和神经炎性疾病的发病机制日益受到重视。 神经退行性疾病，如阿尔茨海默病(AD)。透明质酸(HA)，一种血管生成的调节剂 炎症，是一种非硫酸化的糖胺多糖，由重复的二糖组成，是主要的细胞外基质 脑微血管和脑实质的组成部分。AD神经病理学的特点是 斑块、缠结和紊乱的微血管系统，但对HA和HA之间的关系知之甚少 阿尔茨海默病的微血管和神经病理改变。研究表明，HA在体内的积累增加 AD中的脊髓液，在AD斑块的区域发生改变，但方向和大小受到 缺乏特异性HA标记物、性别差异和同时存在大血管病变。 HA是脑实质中普遍存在的成分，是可访问和可修改的。哈是新来的 由膜结合的HA合成酶(HASE 1-3)以高相对分子质量形式(例如，1000 kDa)合成，即 不断被透明质酸酶(HYALs，主要是1-3种异构体)降解。HA具有大小依赖的影响 低分子量透明质酸(例如，50kDA)的细胞行为直接或通过透明质酸引起神经炎性反应 刺激细胞因子的释放。反过来，炎症又是神经退化的主要驱动因素。因此，医管局 可能在AD的炎症环境中起作用。更好地了解房委会与 AD的微血管和神经病理学是必要的，以确定ECM和HA 具体地说，是AD合乎逻辑的治疗靶点。 假设：HA是神经退行性疾病炎症的驱动因素，因此HA水平 与AD微血管病理和神经病理增加相关。一个具有良好特征的存储库 来自70-101岁(平均85岁)受试者的额叶皮质组织，先前检查了定量A？和 Tau和淀粉样血管病，将被利用。切片将不会有血管梗塞。所有的受试者都有 死前确定的临床痴呆的存在或不存在。到研究结束时，有近200个样本的“没有” (CERAD=0；Braak=0-2)、“中度”(CERAD=2；Braak=3-4)或“重度”AD神经路径(CERAD=3；Braak 5-6)将 研究的目的有三：1)确定阿尔茨海默病的神经病理、神经炎症和 HA积聚；2)检查毛细血管(血管密度、增殖和紧密连接 蛋白质)在AD神经病理中的作用及其与HA蓄积的关系(反映合成和降解)； 以及3)定义HA积聚和淀粉样血管病之间的空间关系，一个独立但相关的 病理学，在脑微血管系统中。HA是否影响病理与临床的一致性 痴呆症的诊断也将被确立。这项研究集中在一个研究不足的领域，具有重要意义- 分析组织学特征是了解HA在AD发病机制中的潜在作用的基础。 以确定HA是否是治疗AD的合理靶点。

The extracellular matrix (ECM) and neuroinflammation are increasingly implicated in the pathogenesis of neurodegenerative diseases, such as Alzheimer's Disease (AD). Hyaluronan (HA), a modulator of inflammation, is a non-sulfated glycosaminoglycan comprised of repeating disaccharides that is the major ECM component of the brain microvasculature and brain parenchyma. AD neuropathology is characterized by plaques, tangles and a disordered microvasculature, but little is known about the relationship between HA and the microvascular and neuropathologic findings of AD. Studies indicate that HA accumulation increases in the spinal fluid in AD and is altered in regions of AD plaques, but the direction and magnitude are confounded by lack of specific HA markers, gender differences and the presence of concurrent macrovascular pathology. HA is a ubiquitous component of brain parenchyma that is accessible and modifiable. HA is newly synthesized by membrane-bound HA synthases (HASes 1-3) in a high MW form (e.g., 1000kDa) that is constantly degraded by hyaluronidases (HYALs, primarily isoforms 1-3.) HA has size-dependent effects on cell behavior with low MW HA (e.g., 50kDA) forms that are neuroinflammatory, both directly and through HA stimulation of cytokine release. Inflammation, in turn, is a major driver of neurodegeneration. As such, HA could contribute to the inflammatory environment in AD. A better understanding of the association of HA with the microvasculature and neuropathology of AD is necessary in order to determine if the ECM, and HA specifically, is a logical therapeutic target in AD. The hypothesis: HA is a driver of inflammation in neurodegenerative diseases, such that HA levels associate with increased AD microvascular pathology and neuropathology. A well-characterized repository of frontal cortex tissues from subjects aged 70-101 years (mean 85), previously examined for quantitative Aß and tau and amyloid angiopathy, will be utilized. Sections will have no vascular infarcts. All subjects have had the presence or absence of clinical dementia determined antemortem. By study end, nearly 200 samples with “no” (Cerad=0; Braak=0-2), “moderate” (Cerad=2; Braak=3-4) or “severe” AD neuropath (Cerad=3; Braak 5-6) will be examined in 3 aims: 1) determine the association between neuropathology of AD, neuroinflammation and HA accumulation; 2) examine the capillary microvasculature (vessel density, proliferation and tight junction proteins) in AD neuropathology and its relationship to HA accumulation (reflecting synthesis and degradation); and 3) define the spatial relationship between HA accumulation and amyloid angiopathy, a separate but related pathology, in the brain microvasculature. Whether HA impacts concordance between pathology and the clinical diagnosis of dementia will also be established. This study focuses on an understudied area and is significant - analyzing histologic features is fundamental to understanding the potential role of HA in AD pathogenesis, and to determine if HA is a logical therapeutic target in AD.