CXCL1 Triggers Caspase-3 Dependent Tau Cleavage in Long-Term Neuronal Cultures and in the Hippocampus of Aged Mice: Implications in Alzheimer’s Disease

Article type: Research Article

Authors: Zhang, Xiao-Fang^a | Zhao, Yan-Feng^b | Zhu, Shun-Wei^c | Huang, Wei-Jie^c | Luo, Yan^c | Chen, Qing-Ying^c | Ge, Li-Jun^d | Li, Run-Sheng^b | Wang, Jian-Fei^d | Sun, Mu^c | Xiao, Zhi-Cheng^{a; e; *} | Fan, Guo-Huang^{b; f; g; h; *}

Affiliations: [a] The Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming, China | [b] Neuroinflammation DPU, GlaxoSmithKline R&D Center, Shanghai, China | [c] Neurodegeneration DPU, GlaxoSmithKline R&D Center, Shanghai, China | [d] Department of Laboratory Animal Sciences, Platform Technology Sciences, GlaxoSmithKline R&D Center, Shanghai, China | [e] Shunxi-Monash Immune Regeneration and Neuroscience Laboratories, Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia | [f] Tongji University School of Life Sciences and Technology, Shanghai, China | [g] Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China | [h] Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA

Correspondence: [*] Correspondence to: Dr. Guo-Huang Fan, Building 3, No. 898 Halei Road, Zhangjiang High-tech Park, Pudong District, Shanghai 201203, China. Tel.: +86 18602112274; Fax: +86 2161590844; E-mail: [email protected]

Correspondence: [*] Correspondence to: Dr. Zhi-Cheng Xiao, Level 3, BIg 75 Monash University, Clayton 3800, VIC, Australia. Tel.: +43 3403266; Fax: +43 61399050680; [email protected]

Abstract: Truncation of tau protein is considered an early event in Alzheimer’s disease (AD) and is believed to play a major pathogenic role in sporadic AD. However, causative factors that trigger tau truncation in AD remain poorly understood. In the present study, we demonstrate that CXCL1 (C-X-C motif ligand 1), a specific ligand for the chemokine receptor CXCR2, induced cleavage of tau at ASP421 in a caspase-3-dependent manner in long-term but not short-term cultured neurons. The cleaved tau formed varicosities or bead-like structures along the neurites, an abnormal distribution of tau induced by CXCL1 that has not been observed previously. CXCL1-induced activation of GSK3β and the subsequent phosphorylation of tau preceded and were required for caspase-3 activation and tau cleavage. Moreover, intrahippocampal microinjection of lentiviral CXCL1 induced tau cleavage in hippocampal neurons in aged (15–18 months of age) but not adult mice (5–10 months of age). Our data highlight a new role of CXCR2 in tau cleavage and suggest that targeting CXCR2 may offer therapeutic benefits to patients with AD and potentially other tauopathies.

Keywords: Caspase-3, CXCL1, CXCR2, hippocampal neurons, tau cleavage

DOI: 10.3233/JAD-150041

Journal: Journal of Alzheimer's Disease, vol. 48, no. 1, pp. 89-104, 2015