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ACS Chem Neurosci. 2018 Nov 21;9(11):2731-2740. doi: 10.1021/acschemneuro.8b00161. Epub 2018 Jul 3.

Modulating Protein Phosphatase 2A Rescues Disease Phenotype in Neurodegenerative Tauopathies.

Author information

1
Florey Institute of Neuroscience and Mental Health , Parkville, Melbourne , Victoria 3052 , Australia.
2
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science , La Trobe University , Melbourne , Victoria 3086 , Australia.

Abstract

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 Aβ, which is thought to drive pathology. However, the lack of clinical translation of these Aβ-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) (CuII(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 CuII(gtsm) recovers the cognitive deficits seen in both neurodegenerative models. In both models, markers of tau pathology were significantly reduced with CuII(gtsm) treatment, and in the APP/PS1 model, the levels of Aβ remained unchanged. Analysis of tau kinases (GSK3β 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.

KEYWORDS:

Alzheimer’s disease; copper; metals; neurodegeneration; phosphatase; tau

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