| Objective:Truncation of tau protein is considered as 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. Inflammation in the central nervous system (CNS), an early event in the pathogenesis of AD, has been proposed to play a role in AD pathology. Proinflammatory chemokine CXCL1 and its receptor have been shown to aberrantly elevate in AD patients, and induce tau hyperphosphorylation in neuronal cultures, however, it remains unclear whether CXCR2 plays a role in tau cleavage.Methods:We perform primary cortical and hippocampal neurons for short-term and long-term cultures to investigate if CXCL1 induce caspase-3 activation and tau cleavage in vitro; Also, we generate the lentiviral particles containing empty vector (control) or CXCL1 construct and intrahippocampally (dentate gyrus, DG) micro inject into adult (5-10 months old) and aged (15-18 months old) mice, respectively, in order to identify if CXCL1 could induce tau cleavage in vivo.Results:In the present study, we demonstrate that CXCL1, a specific ligand for the chemokine receptor CXCR2, induced cleavage of tau at ASP421 in a caspase-3-dependent manner in long-term cultured hippocampal neurons. The cleaved tau formed varicosities or beads along the neurites, an abnormal distribution of tau that was not revealed 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 neurons, associated with spatial memory deficits, in aged but not young mice.Conclusion:Our data shed new light on the role of CXCR2 in AD pathogenesis and suggest that targeting CXCR2 may provide therapeutic benefits to AD and probably other tauopathies. |
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