Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115.
Proc Natl Acad Sci U S A. 2018 Feb 6;115(6):E1289-E1298. doi: 10.1073/pnas.1710329115. Epub 2018 Jan 22.
Mixed pathology, with both Alzheimer's disease and vascular abnormalities, is the most common cause of clinical dementia in the elderly. While usually thought to be concurrent diseases, the fact that changes in cerebral blood flow are a prominent early and persistent alteration in Alzheimer's disease raises the possibility that vascular alterations and Alzheimer pathology are more directly linked. Here, we report that aged tau-overexpressing mice develop changes to blood vessels including abnormal, spiraling morphologies; reduced blood vessel diameters; and increased overall blood vessel density in cortex. Blood flow in these vessels was altered, with periods of obstructed flow rarely observed in normal capillaries. These changes were accompanied by cortical atrophy as well as increased expression of angiogenesis-related genes such as , , and in CD31-positive endothelial cells. Interestingly, mice overexpressing nonmutant forms of tau in the absence of frank neurodegeneration also demonstrated similar changes. Furthermore, many of the genes we observe in mice are also altered in human RNA datasets from Alzheimer patients, particularly in brain regions classically associated with tau pathology such as the temporal lobe and limbic system regions. Together these data indicate that tau pathological changes in neurons can impact brain endothelial cell biology, altering the integrity of the brain's microvasculature.
混合病理学，既有阿尔茨海默病又有血管异常，是老年人临床痴呆最常见的原因。虽然通常认为这是两种并存的疾病，但阿尔茨海默病中脑血流变化是早期和持续存在的突出改变这一事实，使得血管改变和阿尔茨海默病病理学之间的联系更加紧密。在这里，我们报告说，衰老的过度表达 tau 的小鼠会发生血管变化，包括异常的螺旋形态；血管直径减小；大脑皮层中的总血管密度增加。这些血管中的血流发生了改变，在正常毛细血管中很少观察到血流阻塞的时期。这些变化伴随着皮质萎缩，以及血管生成相关基因的表达增加，如在 CD31 阳性内皮细胞中表达的 、 和 。有趣的是，即使没有明显的神经退行性变，过度表达非突变形式 tau 的小鼠也表现出类似的变化。此外，我们在小鼠中观察到的许多基因也在阿尔茨海默病患者的人类 RNA 数据集发生改变，特别是在与 tau 病理学相关的大脑区域，如颞叶和边缘系统区域。这些数据表明，神经元中的 tau 病理变化会影响脑内皮细胞生物学，改变大脑微血管的完整性。
