Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK.
Faculty of Medical and Human Sciences, Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, UK.
Neuropathol Appl Neurobiol. 2017 Feb;43(2):167-182. doi: 10.1111/nan.12295. Epub 2015 Nov 30.
Although changes in extracellular matrix (ECM) scaffold have been reported previously in Alzheimer's disease (AD) compared to normal ageing, it is not known how alterations in the numerous components of the perivascular ECM might occur at different stages of AD. This study therefore investigates potential changes in basement membrane-associated ECM molecules in relation to increasing Braak stages.
Thirty patients were divided into three groups (control subject, subclinical AD and AD patients). ECM levels of collagen IV, perlecan and fibronectin as well as human platelet endothelial cell adhesion molecule (hPECAM) were quantified by immunohistochemistry. Von Willebrand factor staining was measured to assess vessel density. Expression levels were correlated with the presence of amyloid plaques.
Collagen IV, perlecan and fibronectin expression was increased in subclinical AD and AD patients when compared to controls, in frontal and temporal cortex, whilst no further increase was detected between subclinical AD and AD. These changes were not associated with an increase in vessel density, which was instead decreased in the temporal cortex of AD patients. In contrast, hPECAM levels remained unchanged. Finally, we found similar pattern in levels of amyloid deposition between the different Braak stages and showed that changes in ECM components correlated with amyloid deposition.
Present data support the hypothesis that significant ECM changes occur during the early stages of AD. ECM changes affecting brain microvascular functions could therefore drive disease progression and provide potential new early investigational biomarkers in AD.
尽管先前已有研究报道阿尔茨海默病（AD）患者的细胞外基质（ECM）支架发生变化，但尚不清楚在 AD 的不同阶段，众多血管周围 ECM 成分的改变是如何发生的。因此，本研究旨在调查与 Braak 分期增加相关的基膜相关 ECM 分子的潜在变化。
30 名患者被分为三组（对照组、亚临床 AD 患者和 AD 患者）。通过免疫组织化学定量检测胶原 IV、perlecan 和纤维连接蛋白以及人血小板内皮细胞黏附分子（hPECAM）的 ECM 水平。测量血管内皮生长因子（von Willebrand factor，vWF）染色以评估血管密度。表达水平与淀粉样斑块的存在相关。
与对照组相比，亚临床 AD 和 AD 患者的额颞叶皮质中胶原 IV、perlecan 和纤维连接蛋白表达增加，而亚临床 AD 和 AD 之间没有进一步增加。这些变化与血管密度的增加无关，AD 患者的颞叶皮质血管密度反而降低。相比之下，hPECAM 水平保持不变。最后，我们在不同 Braak 分期的淀粉样蛋白沉积水平之间发现了类似的模式，并表明 ECM 成分的变化与淀粉样蛋白沉积相关。
目前的数据支持 ECM 在 AD 早期发生重大变化的假设。影响脑微血管功能的 ECM 变化可能会推动疾病进展，并为 AD 提供潜在的新的早期研究生物标志物。
