Abstract
Although many reports have revealed the importance of defective microglia-mediated amyloid β phagocytosis in Alzheimer’s disease (AD), the underlying mechanism remains to be explored. Here we demonstrate that neurons in the brains of patients with AD and AD mice show reduction of sphingosine kinase1 (SphK1), leading to defective microglial phagocytosis and dysfunction of inflammation resolution due to decreased secretion of specialized proresolving mediators (SPMs). Elevation of SphK1 increased SPMs secretion, especially 15-R-Lipoxin A4, by promoting acetylation of serine residue 565 (S565) of cyclooxygenase2 (COX2) using acetyl-CoA, resulting in improvement of AD-like pathology in APP/PS1 mice. In contrast, conditional SphK1 deficiency in neurons reduced SPMs secretion and abnormal phagocytosis similar to AD. Together, these results uncover a novel mechanism of SphK1 pathogenesis in AD, in which impaired SPMs secretion leads to defective microglial phagocytosis, and suggests that SphK1 in neurons has acetyl-CoA-dependent cytoplasmic acetyltransferase activity towards COX2.
Highlights
Many reports have revealed the importance of defective microglia-mediated amyloid β phagocytosis in Alzheimer’s disease (AD), the underlying mechanism remains to be explored
sphingosine kinase1 (SphK1) mRNA expression and Sphingosine kinase (SphK) activity were significantly decreased in APP/PS1 neurons compared with WT neurons, there were no significant difference in microglia and astrocytes
Kcat did not differ with changing concentration of sphingosine (Fig. 4c). These results indicated that both sphingosine and acetyl-CoA were needed in SphK1 acetyltransferase activity, suggesting that sphingosine may participate in this catalytic reaction
Summary
Many reports have revealed the importance of defective microglia-mediated amyloid β phagocytosis in Alzheimer’s disease (AD), the underlying mechanism remains to be explored. We demonstrate that neurons in the brains of patients with AD and AD mice show reduction of sphingosine kinase[1] (SphK1), leading to defective microglial phagocytosis and dysfunction of inflammation resolution due to decreased secretion of specialized proresolving mediators (SPMs). Resolution is the final stage of the inflammatory response, and is induced by specialized proresolving mediators (SPMs) including Lipoxin A4 (LxA4), Resolvin E1 (RvE1), and Resolvin D1 (RvD1), known to be produced in microglia[7,8] This results in restoration of microglia function, such as increase of phagocytic microglia, downregulation of pro-inflammatory cytokines, and active clearance of apoptotic cells and debris[1,7]. We demonstrate that SphK1 activation restores SPMs secretion in AD patient-specific neurons, suggesting an important role of neuronal SphK1 as a regulator of microglial phagocytosis in AD, and indicating its potential therapeutic use for AD
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