Co-Expression of Three Wild-Type 3R-Tau Isoforms Induces Memory Deficit via Oxidation-Related DNA Damage and Cell Death: A Promising Model for Tauopathies

Article type: Research Article

Authors: Xu, Cheng^a | Guo, Jing^a | Li, Li^{a; b} | Wang, Xin^a | Zhou, Qiuzhi^a | Sun, Dongsheng^a | Zhang, Shujuan^a | Li, Shihong^a | Ye, Jinwang^a | Liu, Yanchao^a | Liu, Enjie^a | Zeng, Peng^a | Wang, Xiaochuan^a | Yang, Ying^a | Wang, Jian-Zhi^{a; c; *}

Affiliations: [a] Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China | [b] Department of Physiology, Hubei University of Chinese Medicine, Wuhan, China | [c] Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China

Correspondence: [*] Correspondence to: Jian-Zhi Wang, PhD, Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China. Tel./Fax: +86 27 83693883; E-mail: [email protected].

Abstract:  The three isoforms of 3R-tau are predominantly deposited in neurons bearing neurofibrillary tangles in Alzheimer’s disease (AD), while only 3R-tau accumulation has been detected in Pick’s disease (PiD), suggesting the involvement of 3R-tau in neurodegeneration. However, both the role and the molecular mechanism of 3R-tau in neurodegeneration are elusive. Here, we co-expressed three isoforms of human wild-type 3R-tau in adult mouse hippocampal to mimic the pathologic tau accumulating observed in PiD patients. We found that co-expressing three 3R-tau isoforms induced hyperphosphorylation and accumulation of tau proteins; simultaneously, the mice showed remarkable neuron death with synapse and memory deficits. Further in vitro and in vivo studies demonstrated that co-expressing 3R-tau isoforms caused oxidative stress evidenced by an increased malondialdehyde, and the decreased superoxide dismutase and glutathione peroxidase; the 3R-tau accumulation also induced significant glial activation and DNA double-strand breaks (DSBs). Notably, the toxic effects of 3R-tau accumulation were efficiently reversed by administration of antioxidants Vitamin E (VitE) and Vitamin C (VitC), respectively. These data reveal that intracellular accumulation of 3R-tau isoforms in adult brain induces significant neuron death and memory deficits with the mechanism involving oxidation-mediated DSBs; and the antioxidants VitE and VitC can efficiently attenuate the toxicities of 3R-tau. Given that no significant cell death has been detected in the currently available wild-type tau-accumulating models, co-expressing 3R-tau isoforms could be a promising model for drug development of tauopathies, such as PiD.

Keywords: 3R-tau, DNA double-strand breaks, oxidative stress, tauopathies

DOI: 10.3233/JAD-191132

Journal: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1105-1123, 2020