Yuzwa Scott A, Shan Xiaoyang, Jones Bryan A, Zhao Gang, Woodward Melissa L, Li Xiaojing, Zhu Yanping, McEachern Ernest J, Silverman Michael A, Watson Neil V, Gong Cheng-Xin, Vocadlo David J
Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Dr, Burnaby, BC V5A 1S6, Canada.
Mol Neurodegener. 2014 Oct 26;9:42. doi: 10.1186/1750-1326-9-42.
Amyloid plaques and neurofibrillary tangles (NFTs) are the defining pathological hallmarks of Alzheimer's disease (AD). Increasing the quantity of the O-linked N-acetylglucosamine (O-GlcNAc) post-translational modification of nuclear and cytoplasmic proteins slows neurodegeneration and blocks the formation of NFTs in a tauopathy mouse model. It remains unknown, however, if O-GlcNAc can influence the formation of amyloid plaques in the presence of tau pathology.
We treated double transgenic TAPP mice, which express both mutant human tau and amyloid precursor protein (APP), with a highly selective orally bioavailable inhibitor of the enzyme responsible for removing O-GlcNAc (OGA) to increase O-GlcNAc in the brain. We find that increased O-GlcNAc levels block cognitive decline in the TAPP mice and this effect parallels decreased β-amyloid peptide levels and decreased levels of amyloid plaques.
This study indicates that increased O-GlcNAc can influence β-amyloid pathology in the presence of tau pathology. The findings provide good support for OGA as a promising therapeutic target to alter disease progression in Alzheimer disease.
淀粉样斑块和神经原纤维缠结(NFTs)是阿尔茨海默病(AD)的典型病理特征。在tau蛋白病小鼠模型中,增加核蛋白和细胞质蛋白的O-连接N-乙酰葡糖胺(O-GlcNAc)翻译后修饰的量可减缓神经退行性变并阻止NFTs的形成。然而,在存在tau病理的情况下,O-GlcNAc是否会影响淀粉样斑块的形成仍不清楚。
我们用一种负责去除O-GlcNAc(OGA)的酶的高选择性口服生物可利用抑制剂治疗双转基因TAPP小鼠,该小鼠同时表达突变型人tau蛋白和淀粉样前体蛋白(APP),以增加大脑中的O-GlcNAc。我们发现,O-GlcNAc水平升高可阻止TAPP小鼠的认知能力下降,这种作用与β-淀粉样肽水平降低和淀粉样斑块水平降低相平行。
本研究表明,在存在tau病理的情况下,增加O-GlcNAc可影响β-淀粉样蛋白病理。这些发现为OGA作为改变阿尔茨海默病疾病进展的有前景的治疗靶点提供了有力支持。