Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, British Columbia, V6T 1Z3, Canada.
Pathology and Laboratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, V6T 2B5, Canada.
Alzheimers Res Ther. 2019 May 13;11(1):44. doi: 10.1186/s13195-019-0497-9.
Alzheimer's disease (AD) is defined by amyloid beta (Aβ) plaques and neurofibrillary tangles and characterized by neurodegeneration and memory loss. The majority of AD patients also have Aβ deposition in cerebral vessels known as cerebral amyloid angiopathy (CAA), microhemorrhages, and vascular co-morbidities, suggesting that cerebrovascular dysfunction contributes to AD etiology. Promoting cerebrovascular resilience may therefore be a promising therapeutic or preventative strategy for AD. Plasma high-density lipoproteins (HDL) have several vasoprotective functions and are associated with reduced AD risk in some epidemiological studies and with reduced Aβ deposition and Aβ-induced inflammation in 3D engineered human cerebral vessels. In mice, deficiency of apoA-I, the primary protein component of HDL, increases CAA and cognitive dysfunction, whereas overexpression of apoA-I from its native promoter in liver and intestine has the opposite effect and lessens neuroinflammation. Similarly, acute peripheral administration of HDL reduces soluble Aβ pools in the brain and some studies have observed reduced CAA as well. Here, we expand upon the known effects of plasma HDL in mouse models and in vitro 3D artery models to investigate the interaction of amyloid, astrocytes, and HDL on the cerebrovasculature in APP/PS1 mice.
APP/PS1 mice deficient or hemizygous for Apoa1 were aged to 12 months. Plasma lipids, amyloid plaque deposition, Aβ protein levels, protein and mRNA markers of neuroinflammation, and astrogliosis were assessed using ELISA, qRT-PCR, and immunofluorescence. Contextual and cued fear conditioning were used to assess behavior.
In APP/PS1 mice, complete apoA-I deficiency increased total and vascular Aβ deposition in the cortex but not the hippocampus compared to APP/PS1 littermate controls hemizygous for apoA-I. Markers of both general and vascular neuroinflammation, including Il1b mRNA, ICAM-1 protein, PDGFRβ protein, and GFAP protein, were elevated in apoA-I-deficient APP/PS1 mice. Additionally, apoA-I-deficient APP/PS1 mice had elevated levels of vascular-associated ICAM-1 in the cortex and hippocampus and vascular-associated GFAP in the cortex. A striking observation was that astrocytes associated with cerebral vessels laden with Aβ or associated with Aβ plaques showed increased reactivity in APP/PS1 mice lacking apoA-I. No behavioral changes were observed.
ApoA-I-containing HDL can reduce amyloid pathology and astrocyte reactivity to parenchymal and vascular amyloid in APP/PS1 mice.
阿尔茨海默病（AD）的定义是由β淀粉样蛋白（Aβ）斑块和神经原纤维缠结引起的，并以神经退行性变和记忆丧失为特征。大多数 AD 患者的大脑血管中也存在 Aβ 沉积，称为脑淀粉样血管病（CAA）、微出血和血管合并症，这表明脑血管功能障碍有助于 AD 的发病机制。因此，促进脑血管弹性可能是 AD 的一种有前途的治疗或预防策略。血浆高密度脂蛋白（HDL）具有多种血管保护功能，一些流行病学研究表明其与 AD 风险降低有关，与 3D 工程化人类脑血管中的 Aβ 沉积和 Aβ 诱导的炎症减少有关。在小鼠中，载脂蛋白 A-I（HDL 的主要蛋白成分）缺乏会增加 CAA 和认知功能障碍，而肝和肠中apoA-I 的内源性启动子过表达则有相反的效果，并减轻神经炎症。同样，HDL 的急性外周给药可减少大脑中的可溶性 Aβ 池，一些研究也观察到 CAA 减少。在这里，我们扩展了已知的血浆 HDL 在小鼠模型和体外 3D 动脉模型中的作用，以研究淀粉样蛋白、星形胶质细胞和 HDL 对 APP/PS1 小鼠脑血管的相互作用。
将 12 个月龄的 APP/PS1 小鼠缺乏或半合子 Apoa1 进行老化。使用 ELISA、qRT-PCR 和免疫荧光法评估血浆脂质、淀粉样斑块沉积、Aβ 蛋白水平、神经炎症和星形胶质细胞增生的蛋白和 mRNA 标志物。使用情景和提示性恐惧条件反射来评估行为。
与 APP/PS1 同窝对照的半合子 apoA-I 相比，完全缺乏 apoA-I 会增加皮质中的总 Aβ 和血管 Aβ 沉积，但不会增加海马体中的沉积。包括 Il1b mRNA、ICAM-1 蛋白、PDGFRβ 蛋白和 GFAP 蛋白在内的一般和血管神经炎症标志物在 apoA-I 缺乏的 APP/PS1 小鼠中升高。此外，apoA-I 缺乏的 APP/PS1 小鼠在皮质和海马体中血管相关的 ICAM-1 水平升高，在皮质中血管相关的 GFAP 水平升高。一个引人注目的观察结果是，缺乏 apoA-I 的 APP/PS1 小鼠与载有 Aβ 的脑血管或与 Aβ 斑块相关的星形胶质细胞反应性增强。未观察到行为变化。
载有 apoA-I 的 HDL 可减少 APP/PS1 小鼠的淀粉样蛋白病理和星形胶质细胞对实质和血管淀粉样蛋白的反应性。
Zotero 插件
