George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, Rhode Island; Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island.
Department of Anesthesiology, Yale University, New Haven, Connecticut.
Am J Pathol. 2022 Mar;192(3):426-440. doi: 10.1016/j.ajpath.2021.11.010. Epub 2021 Dec 8.
Cerebral amyloid angiopathy (CAA), characterized by cerebral vascular amyloid accumulation, neuroinflammation, microbleeds, and white matter (WM) degeneration, is a common comorbidity in Alzheimer disease and a prominent contributor to vascular cognitive impairment and dementia. WM loss was recently reported in the corpus callosum (CC) in the rTg-DI rat model of CAA. The current study shows that the CC exhibits a much lower CAA burden compared with the adjacent cortex. Sequential Window Acquisition of All Theoretical Mass Spectra tandem mass spectrometry was used to show specific proteomic changes in the CC with emerging WM loss and compare them with the proteome of adjacent cortical tissue in rTg-DI rats. In the CC, annexin A3, heat shock protein β1, and cystatin C were elevated at 4 months (M) before WM loss and at 12M with evident WM loss. Although annexin A3 and cystatin C were also enhanced in the cortex at 12M, annexin A5 and the leukodystrophy-associated astrocyte proteins megalencephalic leukoencephalopathy with subcortical cysts 1 and GlialCAM were distinctly elevated in the CC. Pathway analysis indicated neurodegeneration of axons, reflected by reduced expression of myelin and neurofilament proteins, was common to the CC and cortex; activation of Tgf-β1 and F2/thrombin was restricted to the CC. This study provides new insights into the proteomic changes that accompany WM loss in the CC of rTg-DI rats.
脑淀粉样血管病（Cerebral amyloid angiopathy，CAA）的特征是脑血管淀粉样物质积累、神经炎症、微出血和白质（White matter，WM）变性，是阿尔茨海默病的常见合并症，也是血管性认知障碍和痴呆的主要原因。最近有研究报道，在 CAA 的 rTg-DI 大鼠模型中，胼胝体（Corpus callosum，CC）存在 WM 丢失的现象。本研究表明，与相邻皮质相比，CC 具有较低的 CAA 负担。序贯窗口采集所有理论质量谱串联质谱法用于显示具有明显 WM 丢失的 CC 中的特定蛋白质组学变化，并将其与 rTg-DI 大鼠相邻皮质组织的蛋白质组进行比较。在 CC 中，在 WM 丢失前 4 个月（Month，M）和 12M 时，膜联蛋白 A3、热休克蛋白 β1 和半胱氨酸蛋白酶抑制剂 C 升高。尽管在 12M 时，CC 和皮质中也增强了膜联蛋白 A3 和半胱氨酸蛋白酶抑制剂 C，但在 CC 中，白细胞减少症相关星形胶质细胞蛋白巨脑白质脑病伴皮质下囊肿 1 和神经胶质细胞黏附分子明显升高。通路分析表明，轴突的神经退行性变，反映为髓鞘和神经丝蛋白表达减少，在 CC 和皮质中都很常见；Tgf-β1 和 F2/凝血酶的激活仅限于 CC。这项研究为 rTg-DI 大鼠 CC 中 WM 丢失所伴随的蛋白质组变化提供了新的见解。
