Amyloid pathology and synaptic loss in pathological aging,Journal of Neurochemistry

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Amyloid pathology and synaptic loss in pathological aging
Journal of Neurochemistry ( IF 4.2 ) Pub Date : 2021-09-02 , DOI: 10.1111/jnc.15487
Eleni Gkanatsiou _{1,

2} , Johanna Nilsson _{1,

2} , Christina E Toomey _{3,

4,

5} , Agathe Vrillon ₆ , Hlin Kvartsberg _{1,

2} , Erik Portelius _{1,

2} , Henrik Zetterberg _{1,

2,

4,

5,

7} , Kaj Blennow _{1,

2} , Ann Brinkmalm _{1,

2} , Tammaryn Lashley _{3,

5} , Gunnar Brinkmalm _{1,

2}

Affiliation

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory dysfunction and cognitive decline. Pathological aging (PA) describes patients who are amyloid-positive but cognitively unimpaired at time of death. Both AD and PA contain amyloid plaques dominated by amyloid β (Aβ) peptides. In this study, we investigated and compared synaptic protein levels, amyloid plaque load, and Aβ peptide patterns between AD and PA. Two cohorts of post-mortem brain tissue were investigated. In the first, consisting of controls, PA, AD, and familial AD (FAD) individuals, synaptic proteins extracted with tris(hydroxymethyl)aminomethane-buffered saline (TBS) were analyzed. In the second, consisting of tissue from AD and PA patients from three different regions (occipital lobe, frontal lobe, and cerebellum), a two-step extraction was performed. Five synaptic proteins were extracted using TBS, and from the remaining portion Aβ peptides were extracted using formic acid. Subsequently, immunoprecipitation with several antibodies targeting different proteins/peptides was performed for both fractions, which were subsequently analyzed by mass spectrometry. The levels of synaptic proteins were lower in AD (and FAD) compared with PA (and controls), confirming synaptic loss in AD patients. The amyloid plaque load was increased in AD compared with PA, and the relative amount of Aβ40 was higher in AD while for Aβ42 it was higher in PA. In AD loss of synaptic function was associated with increased plaque load and increased amounts of Aβ40 compared with PA cases, suggesting that synaptic function is preserved in PA cases even in the presence of Aβ.

中文翻译：

病理性衰老中的淀粉样蛋白病理和突触丢失

阿尔茨海默病 (AD) 是一种神经退行性疾病，其特征是进行性记忆功能障碍和认知能力下降。病理性衰老 (PA) 描述了淀粉样蛋白阳性但在死亡时认知未受损的患者。AD 和 PA 都含有淀粉样蛋白斑块，主要是淀粉样蛋白 β (Aβ) 肽。在这项研究中，我们调查并比较了 AD 和 PA 之间的突触蛋白水平、淀粉样蛋白斑块负荷和 Aβ 肽模式。研究了两组死后脑组织。首先，由对照、PA、AD 和家族性 AD (FAD) 个体组成，分析了用三（羟甲基）氨基甲烷缓冲盐水 (TBS) 提取的突触蛋白。在第二个中，由来自三个不同区域（枕叶、额叶和小脑）的 AD 和 PA 患者的组织组成，进行了两步提取。使用 TBS 提取了五种突触蛋白，并使用甲酸从剩余部分提取了 Aβ 肽。随后，对这两个部分进行了针对不同蛋白质/肽的几种抗体的免疫沉淀，随后通过质谱法进行了分析。与 PA（和对照）相比，AD（和 FAD）中突触蛋白的水平较低，这证实了 AD 患者的突触丧失。与 PA 相比，AD 患者的淀粉样蛋白斑块负荷增加，并且随后进行质谱分析。与 PA（和对照）相比，AD（和 FAD）中突触蛋白的水平较低，这证实了 AD 患者的突触丧失。与 PA 相比，AD 患者的淀粉样蛋白斑块负荷增加，并且随后进行质谱分析。与 PA（和对照）相比，AD（和 FAD）中突触蛋白的水平较低，这证实了 AD 患者的突触丧失。与 PA 相比，AD 患者的淀粉样蛋白斑块负荷增加，并且AD中Aβ40的相对量较高，而PA中Aβ42的相对量较高。在 AD 中，与 PA 病例相比，突触功能的丧失与斑块负荷增加和 Aβ40 量增加有关，这表明即使在 Aβ 存在的情况下，PA 病例的突触功能也得以保留。

更新日期：2021-10-20

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