Distinct brain regional proteome changes in the rTg-DI rat model of cerebral amyloid angiopathy.
Distinct brain regional proteome changes in the rTg-DI rat model of cerebral amyloid angiopathy.
复制标题
DOI：
10.1111/jnc.15463
复制
发表时间：
2021-10
影响因子：
4.7
通讯作者：
Van Nostrand WE
中科院分区：
文献类型：
--
作者：
Schrader JM;Xu F;Van Nostrand WE
脑淀粉样血管病（Cerebral amyloid angiopopathy， CAA）是老年人常见的脑血管疾病，是阿尔茨海默病的常见合并症，以脑血管淀粉样蛋白积聚、脑梗死、微出血、脑出血为特征，是血管性认知障碍和痴呆的重要诱因。在这里，我们研究了rTg-DI大鼠（CAA的临床前模型）几个脑区域中与特定病理特征相关的蛋白质组变化。尽管不同程度的微血管淀粉样蛋白和相关的神经炎症存在于多个脑区，但微出血和小血管闭塞主要局限于rTg-DI大鼠的丘脑区，这表明在该模型中，不同水平的CAA和相关病理发生在不同的脑区。在这里，我们使用SWATHLC-MS/MS，报告了分离脑区域的特异性蛋白质组学分析，并使用途径分析将区域特异性蛋白质组学变化与独特的相关分子途径联系起来。通路分析提示三个区域均存在肿瘤坏死因子α (TNFα)活化、神经系统形态异常和中性粒细胞脱粒。转化生长因子-β1 （TGF-β1）的激活在海马和丘脑中是共同的，它们都具有高CAA负荷，而丘脑具有独特的血栓形成事件，另外还表现出凝血酶的激活和血细胞的聚集。因此，我们对rTg-DI大鼠具有不同caa相关病理的不同脑区发现的脑蛋白质组变化提出了重要的新见解，并提供了与这些区域疾病过程相关的潜在致病机制的新信息。jnc - 2021 - 0187。我们报道了脑淀粉样血管病（CAA）模型rTg-DI大鼠的区域SWATHLC-MS （Sequential Window Acquisition of all Theoretical Mass Spectra-Mass spectrometry）蛋白质组学数据，以及皮质、海马和丘脑的通路分析。每个区域都发生明显的血管Aβ沉积和神经炎症，而只有丘脑发生血栓形成、血管闭塞和脑微出血。蛋白质组学分析揭示了中性粒细胞胞外陷阱（NETs）在丘脑中的独特存在。丘脑微出血区域（左图蓝色）可见大量血管淀粉样蛋白沉积（右图绿色）和NETs标记组蛋白2A（右图红色）。目前的研究结果为CAA血管病变的潜在机制提供了新的见解。
Cerebral amyloid angiopathy (CAA), a prevalent cerebral small vessel disease in the elderly and a common comorbidity of Alzheimer’s disease, is characterized by cerebral vascular amyloid accumulation, cerebral infarction, microbleeds, intracerebral hemorrhages and is a prominent contributor to vascular cognitive impairment and dementia. Here, we investigate proteome changes associated with specific pathological features in several brain regions of rTg-DI rats, a preclinical model of CAA. Whereas varying degrees of microvascular amyloid and associated neuroinflammation are found in several brain regions the presence of microbleeds and occluded small vessels is largely restricted to the thalamic region of rTg-DI rats, indicating different levels of CAA and associated pathologies occur in distinct brain regions in this model. Here, using SWATHLC-MS/MS, we report specific proteomic analysis of isolated brain regions and employ pathway analysis to correlate regionally specific proteomic changes with uniquely implicated molecular pathways. Pathway analysis suggested common activation of tumor necrosis factor α (TNFα), abnormal nervous system morphology and neutrophil degranulation in all three regions. Activation of transforming growth factor-β1 (TGF-β1) was common to the hippocampus and thalamus, which share high CAA loads, while the thalamus which uniquely exhibits thrombotic events additionally displayed activation of thrombin and aggregation of blood cells. Thus, we present significant and new insight into the cerebral proteome changes found in distinct brain regions with differential CAA-related pathologies of rTg-DI rats and provide new information on potential pathogenic mechanisms associated with these regional disease processes. JNC-2021-0187.R1_InThisIssue We report regional SWATHLC-MS (Sequential Window Acquisition of all Theoretical Mass Spectra-Mass spectrometry) proteomics data, and pathway analysis from the cortex, hippocampus, and thalamus of rTg-DI rats, a model of cerebral amyloid angiopathy (CAA). Each region develops significant vascular Aβ deposition and neuroinflammation, while only the thalamus develops thrombosis, vessel occlusion and cerebral microbleeds. Proteomic analysis revealed the presence of neutrophil extracellular traps (NETs) uniquely in the thalamus. In areas of thalamic microbleeds (blue, left panel) numerous vascular amyloid deposits (green, right panel) and NETs marker histone 2A (red, right panel) are found. The present findings provide new insight into the underlying mechanisms of vascular pathologies in CAA.
登录
查看更多内容
在大鼠大脑中脑出血后，生物标志物和药物靶标的发现使用定量蛋白质组学。
DOI：
10.1007/s12031-018-1206-z
发表时间：
2018-12
期刊：
Journal of molecular neuroscience : MN
影响因子：
--
作者：
Deng S;Feng S;Wang W;Zhao F;Gong Y
通讯作者：
Gong Y
影响因子：
5.8
作者：
Boxio R;Wartelle J;Nawrocki-Raby B;Lagrange B;Malleret L;Hirche T;Taggart C;Pacheco Y;Devouassoux G;Bentaher A
通讯作者：
Bentaher A
影响因子：
14.5
作者：
Bereczki, Erika;Branca, Rui M.;Aarsland, Dag
通讯作者：
Aarsland, Dag
影响因子：
8.3
作者：
Case, Nevicia F.;Charlton, Anna;Smith, Eric E.
通讯作者：
Smith, Eric E.
针对阿尔茨海默病的肿瘤坏死因子α。
影响因子：
2.1
作者：
Decourt B;Lahiri DK;Sabbagh MN
通讯作者：
Sabbagh MN