Tsering Wangchen, Philips Jennifer L, Golde Todd E, Villareal Jonathan A, Prokop Stefan
University of Florida.
Emory University.
Res Sq. 2025 Jun 3:rs.3.rs-6649354. doi: 10.21203/rs.3.rs-6649354/v1.
Numerous extracellular matrix (ECM) proteins, referred to as the matrisome, are increased in Alzheimer's disease (AD). We recently demonstrated that many of these proteins colocalize with Aβ plaques and cerebral amyloid angiopathy (CAA), and some are present in dystrophic cellular processes within and around plaques. However, their precise roles in AD pathogenesis and their spatial and temporal distribution in postmortem brain tissue remain incompletely understood. Here, we performed a comprehensive immunohistochemistry analysis on postmortem brain samples spanning the spectrum of AD neuropathological change (ADNC: low, intermediate, and high). We assessed the accumulation of five matrisome proteins (MDK, SPOCK3, COL25aA1, SDC4, and EGFL8) across four brain regions differentially affected in AD (occipital cortex, hippocampus, striatum, and cerebellum), and examined their association with Aβ plaques, CAA, tau neurites, and neurofibrillary tangles (NFT). MDK in plaques increased consistently with ADNC severity across all regions. In contrast, SPOCK3, COL25A1, EGFL8, and SDC4 showed marked accumulation only in the occipital cortex and hippocampus, with sparse presence in the striatum and absence in the cerebellum. Notably, SPOCK3 exhibited pronounced regional specificity, with significantly higher levels in the hippocampus than in other areas. Patterns of plaque staining and degree of colocalization indicate that select matrisome proteins associate with either distinct types of Aβ deposits (e.g, fibrillar and neuritic versus diffuse plaques), while others may correlate more closely with tau pathology and/or dystrophic processes around plaques. Overall, our findings reveal region- and pathology-specific patterns of these matrisome protein accumulation during AD progression. These proteins represent intriguing biomarkers of AD and based on modeling studies represent potential therapeutic targets.
许多被称为基质体的细胞外基质（ECM）蛋白在阿尔茨海默病（AD）中会增加。我们最近证明，这些蛋白中的许多与Aβ斑块和脑淀粉样血管病（CAA）共定位，并且一些存在于斑块内和周围的营养不良性细胞过程中。然而，它们在AD发病机制中的精确作用以及在死后脑组织中的时空分布仍未完全了解。在这里，我们对跨越AD神经病理变化谱（ADNC：低、中、高）的死后脑样本进行了全面的免疫组织化学分析。我们评估了五种基质体蛋白（MDK、SPOCK3、COL25aA1、SDC4和EGFL8）在AD中受影响程度不同的四个脑区（枕叶皮质、海马体、纹状体和小脑）中的积累情况，并检查了它们与Aβ斑块、CAA、tau神经突和神经原纤维缠结（NFT）的关联。斑块中的MDK在所有区域均随ADNC严重程度持续增加。相比之下，SPOCK3、COL25A1、EGFL8和SDC4仅在枕叶皮质和海马体中显示出明显的积累，在纹状体中稀疏存在，在小脑中不存在。值得注意的是，SPOCK3表现出明显的区域特异性，在海马体中的水平明显高于其他区域。斑块染色模式和共定位程度表明，特定的基质体蛋白与不同类型的Aβ沉积物（例如，纤维状和神经炎性斑块与弥漫性斑块）相关，而其他蛋白可能与tau病理学和/或斑块周围的营养不良性过程更密切相关。总体而言，我们的研究结果揭示了这些基质体蛋白在AD进展过程中的区域和病理特异性积累模式。这些蛋白是AD有趣的生物标志物，并且基于模型研究代表了潜在的治疗靶点。
