Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, OR, USA.
Neuroscience Graduate Program, Oregon Health & Science University, Portland, OR, USA.
Sci Rep. 2018 Aug 17;8(1):12389. doi: 10.1038/s41598-018-30779-x.
The deposition of misfolded proteins, including amyloid beta plaques and neurofibrillary tangles is the histopathological hallmark of Alzheimer's disease (AD). The glymphatic system, a brain-wide network of perivascular pathways that supports interstitial solute clearance, is dependent upon expression of the perivascular astroglial water channel aquaporin-4 (AQP4). Impairment of glymphatic function in the aging rodent brain is associated with reduced perivascular AQP4 localization, and in human subjects, reduced perivascular AQP4 localization is associated with AD diagnosis and pathology. Using human transcriptomic data, we demonstrate that expression of perivascular astroglial gene products dystroglycan (DAG1), dystrobrevin (DTNA) and alpha-syntrophin (SNTA1), are associated with dementia status and phosphorylated tau (P-tau) levels in temporal cortex. Gene correlation analysis reveals altered expression of a cluster of potential astrocytic endfoot components in human subjects with dementia, with increased expression associated with temporal cortical P-tau levels. The association between perivascular astroglial gene products, including DTNA and megalencephalic leukoencephalopathy with subcortical cysts 1 (MLC1) with AD status was confirmed in a second human transcriptomic dataset and in human autopsy tissue by Western blot. This suggests changes in the astroglial endfoot domain may underlie vulnerability to protein aggregation in AD.
错误折叠蛋白的沉积，包括淀粉样β斑块和神经原纤维缠结，是阿尔茨海默病（AD）的组织病理学标志。糖质系统是一个支持细胞间隙溶质清除的脑广泛的血管周围途径网络，依赖于血管周围星形胶质细胞水通道 aquaporin-4（AQP4）的表达。在衰老啮齿动物大脑中糖质系统功能的损害与血管周围 AQP4 定位减少有关，而在人类中，血管周围 AQP4 定位减少与 AD 的诊断和病理有关。使用人类转录组数据，我们证明血管周围星形胶质细胞基因产物肌聚糖（DAG1）、肌联蛋白（DTNA）和α-突触核蛋白（SNTA1）的表达与颞叶皮质的痴呆状态和磷酸化 tau（P-tau）水平有关。基因相关性分析显示，在痴呆患者中存在一组潜在的星形胶质细胞终足成分的表达改变，与颞叶皮质 P-tau 水平增加相关。血管周围星形胶质细胞基因产物（包括 DTNA 和巨脑白质脑病伴皮质下囊肿 1（MLC1））与 AD 状态的关联在第二个人类转录组数据集和人类尸检组织中通过 Western blot 得到了证实。这表明星形胶质细胞终足结构的改变可能是 AD 中蛋白聚集易感性的基础。
