School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; Kunming Institute of Zoology, Chinese University of Hong Kong Joint Laboratory of Bioresources and Molecular Research of Common Diseases, Kunmin-Hong Kong, China.
Neurobiol Aging. 2019 May;77:128-143. doi: 10.1016/j.neurobiolaging.2019.01.020. Epub 2019 Jan 30.
Although it was suggested that gangliosides play an important role in the binding of amyloid fragments to neuronal cells, the exact role of gangliosides in Alzheimer's disease (AD) pathology remains unclear. To understand the role of gangliosides in AD pathology in vivo, we crossed st3gal5-deficient (ST3) mice that lack major brain gangliosides GM1, GD1a, GD3, GT1b, and GQ1b with 5XFAD transgenic mice that overexpress 3 mutant human amyloid proteins AP695 and 2 presenilin PS1 genes. We found that ST3 5XFAD mice have a significantly reduced burden of amyloid depositions, low level of neuroinflammation, and did not exhibit neuronal loss or synaptic dysfunction. ST3 5XFAD mice performed significantly better in a cognitive test than wild-type (WT) 5XFAD mice, which was comparable with WT nontransgenic mice. Treatment of WT 5XFAD mice with the sialic acid-specific Limax flavus agglutinin resulted in substantial improvement of AD pathology to a level of ST3 5XFAD mice. Thus, our findings highlight an important role for gangliosides as a target for the treatment of AD.
虽然有人提出神经节苷脂在淀粉样片段与神经元细胞结合中发挥重要作用，但神经节苷脂在阿尔茨海默病（AD）发病机制中的确切作用仍不清楚。为了了解神经节苷脂在 AD 发病机制中的体内作用，我们将缺乏主要脑神经节苷脂 GM1、GD1a、GD3、GT1b 和 GQ1b 的 st3gal5 缺陷（ST3）小鼠与过表达 3 种突变人类淀粉样蛋白 AP695 和 2 种早老素 PS1 基因的 5XFAD 转基因小鼠进行杂交。我们发现，ST3 5XFAD 小鼠的淀粉样沉积负担明显减轻，神经炎症水平较低，且没有出现神经元丢失或突触功能障碍。ST3 5XFAD 小鼠在认知测试中的表现明显优于野生型（WT）5XFAD 小鼠，与 WT 非转基因小鼠相当。用唾液酸特异性 Limax flavus 凝集素处理 WT 5XFAD 小鼠，可使 AD 病理得到显著改善，达到 ST3 5XFAD 小鼠的水平。因此，我们的研究结果强调了神经节苷脂作为 AD 治疗靶点的重要作用。
