Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, 171 64, Stockholm, Sweden.
Department of Otolaryngology Head and Neck Surgery, The First Hospital of Jilin University, Changchun, 130021, China.
Acta Neuropathol Commun. 2022 Jul 4;10(1):96. doi: 10.1186/s40478-022-01398-5.
Cerebrospinal fluid (CSF) biomarkers play an important role in diagnosing Alzheimer's disease (AD) which is characterized by amyloid-β (Aβ) amyloidosis. Here, we used two App knock-in mouse models, App and App, exhibiting AD-like Aβ pathology to analyze how the brain pathologies translate to CSF proteomes by label-free mass spectrometry (MS). This identified several extracellular matrix (ECM) proteins as significantly altered in App knock-in mice. Next, we compared mouse CSF proteomes with previously reported human CSF MS results acquired from patients across the AD spectrum. Intriguingly, the ECM protein decorin was similarly and significantly increased in both App and App mice, strikingly already at three months of age in the App mice and preclinical AD subjects having abnormal CSF-Aβ42 but normal cognition. Notably, in this group of subjects, CSF-decorin levels positively correlated with CSF-Aβ42 levels indicating that the change in CSF-decorin is associated with early Aβ amyloidosis. Importantly, receiver operating characteristic analysis revealed that CSF-decorin can predict a specific AD subtype having innate immune activation and potential choroid plexus dysfunction in the brain. Consistently, in App mice, increased CSF-decorin correlated with both Aβ plaque load and with decorin levels in choroid plexus. In addition, a low concentration of human Aβ42 induces decorin secretion from mouse primary neurons. Interestingly, we finally identify decorin to activate neuronal autophagy through enhancing lysosomal function. Altogether, the increased CSF-decorin levels occurring at an early stage of Aβ amyloidosis in the brain may reflect pathological changes in choroid plexus, present in a subtype of AD subjects.
脑脊液（CSF）生物标志物在诊断阿尔茨海默病（AD）中起着重要作用，AD 的特征是淀粉样蛋白-β（Aβ）淀粉样变。在这里，我们使用两种 APP 敲入小鼠模型，即 APP 和 APP，表现出 AD 样 Aβ 病理学，通过无标记质谱（MS）分析脑病理学如何转化为 CSF 蛋白质组。这鉴定出几种细胞外基质（ECM）蛋白在 APP 敲入小鼠中发生显著改变。接下来，我们将小鼠 CSF 蛋白质组与先前报道的人类 CSF MS 结果进行比较，这些结果是从 AD 谱中的患者中获得的。有趣的是，ECM 蛋白 decorin 在 APP 和 APP 小鼠中均显著且相似地增加，在 APP 小鼠中甚至在 3 个月龄时就已经显著增加，而在具有异常 CSF-Aβ42 但认知正常的临床前 AD 受试者中也是如此。值得注意的是，在该组受试者中，CSF-decorin 水平与 CSF-Aβ42 水平呈正相关，表明 CSF-decorin 的变化与早期 Aβ 淀粉样变有关。重要的是，ROC 分析显示 CSF-decorin 可以预测具有固有免疫激活和潜在脉络丛功能障碍的特定 AD 亚型。一致地，在 APP 小鼠中，增加的 CSF-decorin 与 Aβ 斑块负荷以及脉络丛中的 decorin 水平相关。此外，低浓度的人 Aβ42 诱导小鼠原代神经元分泌 decorin。有趣的是，我们最终确定 decorin 通过增强溶酶体功能激活神经元自噬。总的来说，在大脑中 Aβ 淀粉样变的早期阶段出现的 CSF-decorin 水平升高可能反映了脉络丛的病理变化，存在于 AD 受试者的一个亚型中。
