title: CXCL1 Triggers Caspase-3 Dependent Tau Cleavage in Long-Term Neuronal Cultures and in the Hippocampus of Aged Mice: Implications in Alzheimer's Disease.
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.
authors.affiliation: The Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming, China.
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Zhang
authors.affiliation: Neuroinflammation DPU, GlaxoSmithKline R&D Center, Shanghai, China.
authors.forename: Yan-Feng
authors.initials: YF
authors.lastname: Zhao
authors.affiliation: Neurodegeneration DPU, GlaxoSmithKline R&D Center, Shanghai, China.
authors.forename: Shun-Wei
authors.initials: SW
authors.lastname: Zhu
authors.affiliation: Neurodegeneration DPU, GlaxoSmithKline R&D Center, Shanghai, China.
authors.forename: Wei-Jie
authors.initials: WJ
authors.lastname: Huang
authors.affiliation: Neurodegeneration DPU, GlaxoSmithKline R&D Center, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Neurodegeneration DPU, GlaxoSmithKline R&D Center, Shanghai, China.
authors.forename: Qing-Ying
authors.initials: QY
authors.lastname: Chen
authors.affiliation: Department of Laboratory Animal Sciences, Platform Technology Sciences, GlaxoSmithKline R&D Center, Shanghai, China.
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Ge
authors.affiliation: Neuroinflammation DPU, GlaxoSmithKline R&D Center, Shanghai, China.
authors.forename: Run-Sheng
authors.initials: RS
authors.lastname: Li
authors.affiliation: Department of Laboratory Animal Sciences, Platform Technology Sciences, GlaxoSmithKline R&D Center, Shanghai, China.
authors.forename: Jian-Fei
authors.initials: JF
authors.lastname: Wang
authors.affiliation: Neurodegeneration DPU, GlaxoSmithKline R&D Center, Shanghai, China.
authors.forename: Mu
authors.initials: M
authors.lastname: Sun
authors.affiliation: The Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming, China.|Shunxi-Monash Immune Regeneration and Neuroscience Laboratories, Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia.
authors.forename: Zhi-Cheng
authors.initials: ZC
authors.lastname: Xiao
authors.affiliation: Neuroinflammation DPU, GlaxoSmithKline R&D Center, Shanghai, China.|Tongji University School of Life Sciences and Technology, Shanghai, China.|Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.|Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Guo-Huang
authors.initials: GH
authors.lastname: Fan
mesh_terms: D000375:Aging; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism*; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000097:blood / Q000134:cerebrospinal fluid / Q000235:genetics / Q000494:pharmacology*; D004622:Embryo, Mammalian; D005260:Female; D006624:Hippocampus / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008845:Microinjections; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014162:Transfection; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D054360:Chemokine CXCL1; C513297:Cxcl1 protein, rat; D008869:Microtubule-Associated Proteins; D016875:tau Proteins; D053148:Caspase 3
keywords: CXCL1; CXCR2; Caspase-3; hippocampal neurons; tau cleavage