Modulating Protein Phosphatase 2A Rescues Disease Phenotype in Neurodegenerative Tauopathies

被引:17
|
作者
McKenzie-Nickson, Simon [1 ,2 ]
Chan, Jacky [1 ]
Perez, Keyla [1 ]
Hung, Lin W. [1 ]
Cheng, Lesley [4 ]
Sedjahtera, Amelia [1 ]
Gunawan, Lydia [1 ]
Adlard, Paul A. [1 ]
Hayne, David J. [3 ]
McInnes, Lachlan E. [3 ]
Donnelly, Paul S. [3 ]
Finkelstein, David, I [1 ]
Hill, Andrew F. [4 ]
Barnham, Kevin J. [1 ,2 ]
机构
[1] Florey Inst Neurosci & Mental Hlth, Melbourne, Vic 3052, Australia
[2] Bio21 Mol & Biotechnol Inst, Dept Pharmacol & Therapeut, Melbourne, Vic 3052, Australia
[3] Bio21 Mol & Biotechnol Inst, Sch Chem, Melbourne, Vic 3052, Australia
[4] La Trobe Univ, La Trobe Inst Mol Sci, Dept Biochem & Genet, Melbourne, Vic 3086, Australia
来源
ACS CHEMICAL NEUROSCIENCE | 2018年 / 9卷 / 11期
基金
澳大利亚国家健康与医学研究理事会;
关键词
Alzheimer's disease; tau; phosphatase; copper; neurodegeneration; metals; TAU-MEDIATED NEURODEGENERATION; ALZHEIMERS-DISEASE; AMYLOID-BETA; PHOSPHORYLATED-TAU; HYPERPHOSPHORYLATED-TAU; MOUSE MODEL; LITHIUM; METHYLATION; PP2A; MICE;
D O I
10.1021/acschemneuro.8b00161
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Alzheimer's disease (AD) is the leading cause of dementia worldwide accounting for around 70% of all cases. There is currently no treatment for AD beyond symptom management and attempts at developing disease-modifying therapies have yielded very little. These strategies have traditionally targeted the peptide A beta, which is thought to drive pathology. However, the lack of clinical translation of these A beta-centric strategies underscores the need for diverse treatment strategies targeting other aspects of the disease. Metal dyshomeostasis is a common feature of several neurodegenerative diseases such as AD, Parkinson's disease, and frontotemporal dementia, and manipulation of metal homeostasis has been explored as a potential therapeutic avenue for these diseases. The copper ionophore glyoxalbis-[N4-methylthiosemicarbazonato]Cu(II) (Cu-II(gtsm)) has previously been shown to improve the cognitive deficits seen in an AD animal model; however, the molecular mechanism remained unclear. Here we report that the treatment of two animal tauopathy models (APP/PS1 and rTg4510) with Cu-II(gtsm) recovers the cognitive deficits seen in both neurodegenerative models. In both models, markers of tau pathology were significantly reduced with Cu-II(gtsm) treatment, and in the APP/PS1 model, the levels of A beta remained unchanged. Analysis of tau kinases (GSK3 beta and CDK5) revealed no drug induced changes; however, both models exhibited a significant increase in the levels of the structural subunit of the tau phosphatase, PP2A. These findings suggest that targeting the tau phosphatase PP2A has therapeutic potential for preventing memory impairments and reducing the tau pathology seen in AD and other tauopathies.
引用
收藏
页码:2731 / 2740
页数:19
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