Cerebral amyloid angiopathy (CAA) is characterized by amyloid beta (Aβ) deposition in cerebrovasculature. It is prevalent with aging and Alzheimer’s disease (AD), associated with intracerebral hemorrhage, and contributes to cognitive deficits. To better understand molecular mechanisms, CAA(+) and CAA(−) vessels were microdissected from paraffin-embedded autopsy temporal cortex of age-matched Control (n = 10), mild cognitive impairment (MCI; n = 4), and sporadic AD (n = 6) cases, followed by label-free quantitative mass spectrometry. 257 proteins were differentially abundant in CAA(+) vessels compared to neighboring CAA(−) vessels in MCI, and 289 in AD (p < 0.05, fold-change > 1.5). 84 proteins changed in the same direction in both groups, and many changed in the same direction among proteins significant in at least one group (p < 0.0001, R² = 0.62). In CAA(+) vessels, proteins significantly increased in both AD and MCI were particularly associated with collagen-containing extracellular matrix, while proteins associated with ribonucleoprotein complex were significantly decreased in both AD and MCI. In neighboring CAA(−) vessels, 61 proteins were differentially abundant in MCI, and 112 in AD when compared to Control cases. Increased proteins in CAA(−) vessels were associated with extracellular matrix, external encapsulating structure, and collagen-containing extracellular matrix in MCI; collagen trimer in AD. Twenty two proteins were increased in CAA(−) vessels of both AD and MCI. Comparison of the CAA proteome with published amyloid-plaque proteomic datasets identified many proteins similarly enriched in CAA and plaques, as well as a protein subset hypothesized as preferentially enriched in CAA when compared to plaques. SEMA3G emerged as a CAA specific marker, validated immunohistochemically and with correlation to pathology levels (p < 0.0001; R² = 0.90). Overall, the CAA(−) vessel proteomes indicated changes in vessel integrity in AD and MCI in the absence of Aβ, and the CAA(+) vessel proteome was similar in MCI and AD, which was associated with vascular matrix reorganization, protein translation deficits, and blood brain barrier breakdown.

脑淀粉样血管病 (CAA) 的特征是脑血管系统中淀粉样蛋白 (Aβ) 沉积。它在衰老和阿尔茨海默病 (AD) 中普遍存在，与脑出血相关，并导致认知缺陷。为了更好地了解分子机制，从年龄匹配的对照（ n = 10）、轻度认知障碍（MCI； n = 4）和散发性 AD 的石蜡包埋尸检颞叶皮质中显微解剖 CAA（+）和 CAA（−）血管( n = 6) 例，然后进行无标记定量质谱分析。与 MCI 中邻近的 CAA(-) 血管相比，CAA(+) 血管中有 257 种蛋白质丰度存在差异，AD 中则有 289 种蛋白质（ p < 0.05，倍数变化 > 1.5）。两组中有 84 种蛋白质发生了相同方向的变化，并且至少在一组中显着的蛋白质中许多蛋白质发生了相同方向的变化 ( p < 0.0001， R ² = 0.62)。在CAA(+)血管中，AD和MCI中与含有胶原蛋白的细胞外基质相关的蛋白质显着增加，而与核糖核蛋白复合物相关的蛋白质在AD和MCI中显着减少。与对照病例相比，在邻近的 CAA(−) 血管中，MCI 中的 61 种蛋白质丰度存在差异，AD 中的 112 种蛋白质丰度存在差异。 CAA(−) 血管中蛋白质的增加与 MCI 中的细胞外基质、外部封装结构和含有胶原蛋白的细胞外基质有关； AD 中的胶原三聚体。 AD 和 MCI 的 CAA(−) 血管中有 22 种蛋白质增加。 将 CAA 蛋白质组与已发表的淀粉样斑块蛋白质组数据集进行比较，发现了许多在 CAA 和斑块中类似富集的蛋白质，以及假设与斑块相比在 CAA 中优先富集的蛋白质子集。 SEMA3G 作为 CAA 特异性标记物出现，经过免疫组织化学验证并与病理水平相关 ( p < 0.0001； R ² = 0.90)。总体而言，CAA（−）血管蛋白质组表明在缺乏Aβ的情况下AD和MCI中血管完整性发生变化，而MCI和AD中CAA（+）血管蛋白质组相似，这与血管基质重组、蛋白质翻译缺陷有关和血脑屏障破坏。