Overexpression of heme oxygenase 1 causes cognitive decline and affects pathways for tauopathy in mice.

Dayong Wang, Yang Hui, Yahui Peng, Lu Tang, Jianfeng Jin, Rongzhang He, Yanze Li, Shuai Zhang, Lisha Li, You Zhou, Jing Li, Ning Ma, Jihong Li, Sijia Li, Xu Gao, Shanshun Luo

Index: J. Alzheimers Dis. 43(2) , 519-34, (2014)

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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.