RRC ID 78631
Author Komai M, Noda Y, Ikeda A, Kaneshiro N, Kamikubo Y, Sakurai T, Uehara T, Takasugi N.
Title Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes.
Journal J Lipid Res
Abstract The link between changes in astrocyte function and the pathological progression of Alzheimer's disease (AD) has attracted considerable attention. Interestingly, activated astrocytes in AD show abnormalities in their lipid content and metabolism. In particular, the expression of apolipoprotein E (ApoE), a lipid transporter, is decreased. Because ApoE has anti-inflammatory and amyloid β (Aβ)-metabolizing effects, the nuclear receptors, retinoid X receptor (RXR) and LXR, which are involved in ApoE expression, are considered promising therapeutic targets for AD. However, the therapeutic effects of agents targeting these receptors are limited or vary considerably among groups, indicating the involvement of an unknown pathological factor that modifies astrocyte and ApoE function. Here, we focused on the signaling lipid, sphingosine-1-phosphate (S1P), which is mainly produced by sphingosine kinase 2 (SphK2) in the brain. Using astrocyte models, we found that upregulation of SphK2/S1P signaling suppressed ApoE induction by both RXR and LXR agonists. We also found that SphK2 activation reduced RXR binding to the APOE promoter region in the nucleus, suggesting the nuclear function of SphK2/S1P. Intriguingly, suppression of SphK2 activity by RNA knockdown or specific inhibitors upregulated lipidated ApoE induction. Furthermore, the induced ApoE facilitates Aβ uptake in astrocytes. Together with our previous findings that SphK2 activity is upregulated in AD brain and promotes Aβ production in neurons, these results indicate that SphK2/S1P signaling is a promising multifunctional therapeutic target for AD that can modulate astrocyte function by stabilizing the effects of RXR and LXR agonists, and simultaneously regulate neuronal pathogenesis.
Volume 65(3)
Pages 100510
Published 2024-3-1
DOI 10.1016/j.jlr.2024.100510
PII S0022-2275(24)00015-4
PMID 38280459
PMC PMC10907773
MeSH Alzheimer Disease* / metabolism Amyloid beta-Peptides* / metabolism Apolipoproteins E / metabolism Astrocytes / metabolism Brain / metabolism Humans
DNA material pCAGGS-BLRP-BirA (RDB15774)