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Selective reduction of astrocyte apoE3 and apoE4 strongly reduces Aβ accumulation and plaque-related pathology in a mouse model of amyloidosis
Molecular Neurodegeneration ( IF 14.9 ) Pub Date : 2022-02-02 , DOI: 10.1186/s13024-022-00516-0
Thomas E Mahan 1 , Chao Wang 1 , Xin Bao 1 , Ankit Choudhury 1 , Jason D Ulrich 1 , David M Holtzman 1
Affiliation  

One of the key pathological hallmarks of Alzheimer disease (AD) is the accumulation of the amyloid-β (Aβ) peptide into amyloid plaques. The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset AD and has been shown to influence the accumulation of Aβ in the brain in an isoform-dependent manner. ApoE can be produced by different cell types in the brain, with astrocytes being the largest producer of apoE, although reactive microglia also express high levels of apoE. While studies have shown that altering apoE levels in the brain can influence the development of Aβ plaque pathology, it is not fully known how apoE produced by specific cell types, such as astrocytes, contributes to amyloid pathology. We utilized APOE knock-in mice capable of having APOE selectively removed from astrocytes in a tamoxifen-inducible manner and crossed them with the APP/PS1-21 mouse model of amyloidosis. We analyzed the changes to Aβ plaque levels and assessed the impact on cellular responses to Aβ plaques when astrocytic APOE is removed. Tamoxifen administration was capable of strongly reducing apoE levels in the brain by markedly reducing astrocyte apoE, while microglial apoE expression remained. Reduction of astrocytic apoE3 and apoE4 led to a large decrease in Aβ plaque deposition and less compact plaques. While overall Iba1+ microglia were unchanged in the cortex after reducing astrocyte apoE, the expression of the disease-associated microglial markers Clec7a and apoE were lower around amyloid plaques, indicating decreased microglial activation. Additionally, astrocyte GFAP levels are unchanged around amyloid plaques, but overall GFAP levels are reduced in the cortex of female apoE4 mice after a reduction in astrocytic apoE. Finally, while the amount of neuritic dystrophy around remaining individual plaques was increased with the removal of astrocytic apoE, the overall amount of cortical amyloid-associated neuritic dystrophy was significantly decreased. This study reveals an important role of astrocytic apoE3 and apoE4 on the deposition and accumulation of Aβ plaques as well as on certain Aβ-associated downstream effects.

中文翻译:

星形胶质细胞 apoE3 和 apoE4 的选择性减少强烈减少淀粉样变性小鼠模型中的 Aβ 积累和斑块相关病理学

阿尔茨海默病 (AD) 的关键病理特征之一是淀粉样蛋白-β (Aβ) 肽积累到淀粉样蛋白斑块中。载脂蛋白 E (APOE) 基因是迟发性 AD 最强的遗传风险因素,已被证明以异构体依赖性方式影响大脑中 Aβ 的积累。ApoE 可以由大脑中的不同细胞类型产生,星形胶质细胞是最大的 apoE 产生者,尽管反应性小胶质细胞也表达高水平的 apoE。虽然研究表明改变大脑中的 apoE 水平可以影响 Aβ 斑块病理学的发展,但尚不完全了解特定细胞类型(如星形胶质细胞)产生的 apoE 如何导致淀粉样蛋白病理学。我们利用能够以他莫昔芬诱导的方式从星形胶质细胞中选择性去除 APOE 的 APOE 敲入小鼠,并将它们与淀粉样变性的 APP/PS1-21 小鼠模型杂交。我们分析了 Aβ 斑块水平的变化,并评估了去除星形细胞 APOE 后对 Aβ 斑块细胞反应的影响。他莫昔芬给药能够通过显着降低星形胶质细胞 apoE 来强烈降低大脑中的 apoE 水平,而小胶质细胞 apoE 表达仍然存在。星形细胞 apoE3 和 apoE4 的减少导致 Aβ 斑块沉积的大量减少和更不致密的斑块。虽然在减少星形胶质细胞 apoE 后,皮质中的整体 Iba1+ 小胶质细胞没有变化,但与疾病相关的小胶质细胞标志物 Clec7a 和 apoE 在淀粉样斑块周围的表达较低,表明小胶质细胞活化减少。此外,星形胶质细胞 GFAP 水平在淀粉样斑块周围没有变化,但在星形细胞 apoE 减少后,雌性 apoE4 小鼠皮质中的总体 GFAP 水平降低。最后,虽然剩余单个斑块周围的神经炎性营养不良的数量随着星形细胞 apoE 的去除而增加,但皮质淀粉样蛋白相关的神经炎性营养不良的总量显着降低。这项研究揭示了星形胶质细胞 apoE3 和 apoE4 在 Aβ 斑块的沉积和积累以及某些 Aβ 相关的下游效应中的重要作用。虽然随着星形细胞 apoE 的去除,剩余单个斑块周围的神经炎性营养不良数量增加,但与皮质淀粉样蛋白相关的神经炎性营养不良的总量显着降低。这项研究揭示了星形胶质细胞 apoE3 和 apoE4 在 Aβ 斑块的沉积和积累以及某些 Aβ 相关的下游效应中的重要作用。虽然随着星形细胞 apoE 的去除,剩余单个斑块周围的神经炎性营养不良数量增加,但与皮质淀粉样蛋白相关的神经炎性营养不良的总量显着降低。这项研究揭示了星形胶质细胞 apoE3 和 apoE4 在 Aβ 斑块的沉积和积累以及某些 Aβ 相关的下游效应中的重要作用。
更新日期:2022-02-03
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