Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital/Mölndal, S-431 80, Mölndal, Sweden.
Queen Square Brain Bank for Neurological Disorders, Department of Movement Disorders, UCL Institute of Neurology, London, UK.
Acta Neuropathol. 2019 Jan;137(1):89-102. doi: 10.1007/s00401-018-1910-3. Epub 2018 Sep 22.
Synaptic degeneration and neuronal loss are early events in Alzheimer's disease (AD), occurring long before symptom onset, thus making synaptic biomarkers relevant for enabling early diagnosis. The postsynaptic protein neurogranin (Ng) is a cerebrospinal fluid (CSF) biomarker for AD, also in the prodromal phase. Here we tested the hypothesis that during AD neurodegeneration, processing of full-length Ng into endogenous peptides in the brain is increased. We characterized Ng in post-mortem brain tissue and investigated the levels of endogenous Ng peptides in relation to full-length protein in brain tissue of patients with sporadic (sAD) and familial Alzheimer's disease (fAD), healthy controls and individuals who were cognitively unaffected but amyloid-positive (CU-AP) in two different brain regions. Brain tissue from parietal cortex [sAD (n = 10) and age-matched controls (n = 10)] and temporal cortex [sAD (n = 9), fAD (n = 10), CU-AP (n = 13) and controls (n = 9)] were included and all the samples were analyzed by three different methods. Using high-resolution mass spectrometry, 39 endogenous Ng peptides were identified while full-length Ng was found to be modified including disulfide bridges or glutathione. In sAD parietal cortex, the ratio of peptide-to-total full-length Ng was significantly increased for eight endogenous Ng peptides compared to controls. In the temporal cortex, several of the peptide-to-total full-length Ng ratios were increased in both sAD and fAD cases compared to controls and CU-AP. This finding was confirmed by western blot, which mainly detects full-length Ng, and enzyme-linked immunosorbent assay, most likely detecting a mix of peptides and full-length Ng. In addition, Ng was significantly associated with the degree of amyloid and tau pathology. These results suggest that processing of Ng into peptides is increased in AD brain tissue, which may reflect the ongoing synaptic degeneration, and which is also mirrored as increased levels of Ng peptides in CSF.
突触退化和神经元丢失是阿尔茨海默病（AD）的早期事件，早在症状出现之前就已经发生，因此突触生物标志物与早期诊断相关。突触后蛋白神经颗粒蛋白（Ng）是 AD 的脑脊液（CSF）生物标志物，在前驱期也是如此。在这里，我们检验了一个假设，即在 AD 神经退行性变过程中，大脑中全长 Ng 被加工成内源性肽的过程会增加。我们对死后脑组织中的 Ng 进行了特征描述，并研究了与脑组织中全长蛋白相关的内源性 Ng 肽水平，这些组织来自散发性 AD（sAD）和家族性 AD（fAD）患者、健康对照者以及认知功能正常但淀粉样蛋白阳性（CU-AP）的个体，这两种情况分别取自两个不同的脑区。包含额皮质（sAD [n = 10] 和年龄匹配的对照者 [n = 10]）和颞皮质（sAD [n = 9]、fAD [n = 10]、CU-AP [n = 13] 和对照者 [n = 9]）的脑组织被纳入研究，所有样本都用三种不同的方法进行了分析。利用高分辨率质谱，共鉴定到 39 种内源性 Ng 肽，同时全长 Ng 被发现发生了修饰，包括二硫键或谷胱甘肽。在 sAD 额皮质中，与对照者相比，全长 Ng 被加工成 8 种内源性 Ng 肽的比例显著增加。在颞皮质中，与对照者和 CU-AP 相比，sAD 和 fAD 病例中几种肽与全长 Ng 的比值均增加。这一发现通过主要检测全长 Ng 的 Western blot 和可能检测到肽和全长 Ng 混合物的酶联免疫吸附试验得到了证实。此外，Ng 与淀粉样蛋白和 tau 病理的严重程度显著相关。这些结果表明，AD 脑组织中 Ng 被加工成肽的过程增加，这可能反映了持续的突触退化，这也反映在 CSF 中 Ng 肽水平增加。
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