Overexpression of Heme Oxygenase 1 Impairs Cognitive Ability and Changes the Plasticity of the Synapse

Article type: Research Article

Authors: Li, Lisha^{a; b; c; 1} | Peng, Yahui^{a; b; c; 1} | Hui, Yang^{a; b; c; *} | Zhang, Shuai^a | Zhou, You^a | Li, Dan^d | Li, Jihong^{a; b; c} | Si, Zizhen^a | Li, Jing^a | Wang, Dayong^{a; b; c} | Li, Yanze^{a; b; c} | Dong, Min^e | Gao, Xu^{a; b; c; *}

Affiliations: [a] Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China | [b] State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Harbin, China | [c] Key Laboratory of Cardiovascular Medicine Research (Harbin Medical University), Ministry of Education, Harbin, China | [d] People’s Hospital of Yuxi City, Yuki, China | [e] GE Healthcare Life Sciences, Shanghai, China

Correspondence: [*] Correspondence to: Xu Gao, Department of Biochemistry and Molecular Biology, Harbin Medical University, 194 XueFu Road Nangang Dist, Harbin 150086, P.R. China. Tel./Fax: +86 451 8708 6131; gaoxu6712@163.com (X. Gao)

Correspondence: [*] Correspondence to: Yang Hui, Department of Biochemistry and Molecular Biology, Harbin Medical University, 194 XueFu Road Nangang Dist, Harbin 150086, P.R. China. Tel.: +86 451 8667 1684; huiyang79@126.com (Y. Hui)

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

Abstract: The expression of heme oxygenase 1 (HO-1) in the cortex and hippocampus is higher in Alzheimer’s disease (AD) and mild cognitive impairment patients than healthy individuals, and epidemiological studies suggest that HO-1 is an important factor for AD. However, its influence on nerve function is poorly understood. Here, we studied the effect of the overexpression of HO-1 on the cognitive and synaptic plasticity in 3-month-old mice. We found that the overexpression of HO-1 induced spatial learning and memory deficits with an apparent decrease of AMPKR, NMDAR, postsynaptic density protein 95, synapsin I, synaptophysin, and microtubule-associated protein 2, all of which are memory-related synaptic proteins. Concurrently, HO-1 could co-express and induce the aggregation of Aβ 42 and Aβ oligomer in the hippocampus area. Additionally, our research is the first to demonstrate that HO-1 changes the morphology of the synapse to impair the neural circuit. These results indicate that the overexpression of HO-1 can damage synaptic plasticity in early stages to induce AD-like pathology and cognitive abnormality in mice.

Keywords: Alzheimer’s disease, amyloid-β oligomer, dendritic spine, heme oxygenase 1, synaptic plasticity

DOI: 10.3233/JAD-150027

Journal: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 595-608, 2015