Overexpression of Heme Oxygenase 1 Causes Cognitive Decline and Affects Pathways for Tauopathy in Mice

Article type: Research Article

Authors: Wang, Dayong^{a; b; c; 1} | Hui, Yang^{a; b; c; 1} | Peng, Yahui^{a; b; c; 1} | Tang, Lu^{a; b; c} | Jin, Jianfeng^{a; b; c} | He, Rongzhang^{a; b; c} | Li, Yanze^{a; b; c} | Zhang, Shuai^{a; b; c} | Li, Lisha^{a; b; c} | Zhou, You^{a; b; c} | Li, Jing^{a; b; c} | Ma, Ning^{a; b; c} | Li, Jihong^{a; b; c} | Li, Sijia^{a; b; c} | Gao, Xu^{a; b; c; *} | Luo, Shanshun^{d; *}

Affiliations: [a] Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China | [b] Key Laboratory of Cardiovascular Medicine Research (Harbin Medical University), Ministry of Education, Harbin, China | [c] State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Harbin, China | [d] Department of Gerontology, The First Hospital of Harbin Medical University, Harbin, China

Correspondence: [*] Correspondence to: Xu Gao and Shanshun Luo, Harbin Medical University, Harbin, China. Tel.: +86 451 86661684; Fax: +86 451 8708 6131; E-mails: gaoxu6712@163.com (Xu Gao), shanshunluo@163.com (Shanshun Luo).

Note: [1] These authors contributed equally to this work.

Abstract: The stress protein heme oxygenase-1 (HO-1) is upregulated and co-localizes to pathological features, including tauopathies in the brains of individuals with Alzheimer's disease. However, the relationship between HO-1 and Alzheimer's disease remains unclear. In our previous research, the long-term overexpression of HO-1 was shown to promote tau aggregation by inducing tau phosphorylation in the mouse brain. In this study, we found that the long-term overexpression of HO-1 led to cognitive decline in transgenic mice, as determined by the water maze test, and that HO-1 can affect two pathways for tauopathy. Through one pathway, HO-1 promotes the expression of CDK5 by accumulating reactive oxygen species, which are produced by HO-1 downstream products of iron in neuro2a cell lines and mouse brain. Through the second pathway, HO-1 induces tau truncation at D421 in vivo and in vitro. Clearly, there is a HO-1-dependent mechanism responsible for tau protein phosphorylation and tau truncation in vivo and in vitro. Taken together, our results suggest that HO-1 plays an important role in the disease process of tauopathies in AD.

Keywords: Alzheimer's disease, CDK5, heme oxygenase-1, iron, tau truncation, tauopathies

DOI: 10.3233/JAD-140567

Journal: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 519-534, 2015