de Oliveira Ana Pacheco, Baghel Divya, Holcombe Brooke, Chase William, Ward Tyler, Wang Shih-Hsiu J, Ghosh Ayanjeet
Department of Chemistry and Biochemistry, The University of Alabama, Tuscaloosa, AL, 35401, USA.
Departments of Pathology and Neurology, Duke University, Durham, NC, 27710, USA.
Acta Neuropathol. 2025 Jul 13;150(1):3. doi: 10.1007/s00401-025-02911-5.
Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder marked by amyloid-β (Aβ) deposition in blood vessel walls, leading to hemorrhage and recurring stroke. Despite significant overlap with Alzheimer's disease (AD) through shared Aβ pathology, the specific structural characteristics of Aβ aggregates in CAA and their variations between stages of disease severity are yet to be fully understood. Traditional approaches relying on brain-derived fibrils can potentially overlook the polymorphic heterogeneity and chemical associations within vascular amyloids. This study utilizes sub-diffraction, label-free optical photothermal infrared (O-PTIR) spectroscopic imaging to directly probe the chemical structure and heterogeneity of vascular amyloid aggregates within human brain tissues across different CAA stages. Our results demonstrate a clear increase in β-sheet content within vascular Aβ deposits corresponding to disease progression. Crucially, we identify a significant presence of antiparallel β-sheet structures, particularly prevalent in moderate/severe CAA. The abundance of antiparallel structures correlates strongly with co-localized lipids, implicating a lipid-mediated aggregation mechanism. We substantiate the ex-vivo observations using nanoscale AFM-IR spectroscopy and demonstrate that Aβ40 aggregated in-vitro with brain-derived lipids adopts antiparallel structural distributions mirroring those found in CAA vascular lesions. This work provides critical insights into the structural distributions of Aβ aggregates in CAA, highlighting the presence of polymorphs typically associated with transient intermediates, which may lead to alternate mechanisms for neurotoxicity.
脑淀粉样血管病（CAA）是一种脑血管疾病，其特征是淀粉样β蛋白（Aβ）沉积在血管壁中，导致出血和复发性中风。尽管通过共享的Aβ病理学与阿尔茨海默病（AD）有显著重叠，但CAA中Aβ聚集体的特定结构特征及其在疾病严重程度不同阶段的变化尚未完全了解。依赖于脑源性纤维的传统方法可能会忽略血管淀粉样蛋白内的多态性异质性和化学关联。本研究利用亚衍射、无标记光热红外（O-PTIR）光谱成像直接探测不同CAA阶段人脑组织内血管淀粉样聚集体的化学结构和异质性。我们的结果表明，随着疾病进展，血管Aβ沉积物中的β-折叠含量明显增加。至关重要的是，我们发现了大量反平行β-折叠结构，尤其在中度/重度CAA中普遍存在。反平行结构的丰度与共定位脂质密切相关，这意味着存在脂质介导的聚集机制。我们使用纳米级原子力显微镜红外光谱法证实了体外观察结果，并证明在体外与脑源性脂质聚集的Aβ40呈现出与CAA血管病变中发现的反平行结构分布相似的情况。这项工作为CAA中Aβ聚集体的结构分布提供了关键见解，突出了通常与瞬时中间体相关的多晶型物的存在，这可能导致神经毒性的替代机制。
