CXCL1 triggers caspase-3 dependent tau cleavage in long-term neuronal cultures and in the hippocampus of aged mice: Implications in Alzheimer's disease

Xiao-Fang Zhang, Yan-Feng Zhao, Shun-Wei Zhu, Wei-Jie Huang, Yan Luo, Qing-Ying Chen, Li-Jun Ge, Run-Shen Li, Jian-Fei Wang, Mu Sun, Zhi-Cheng Xiao, Guo-Huang Fan

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5 Citations (Scopus)

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 GSK3beta 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.
Original languageEnglish
Pages (from-to)89 - 104
Number of pages16
JournalJournal of Alzheimer's Disease
Volume48
Issue number1
DOIs
Publication statusPublished - 2015

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