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Lipoprotein receptor-related protein-6 protects the brain from ischemic injury.

ABSTRACT: Loss-of-function mutations of the lipoprotein receptor-related protein-6 (LRP6), a coreceptor in the Wingless-related integration site-?-catenin prosurvival pathway, have been implicated in myocardial ischemia and neurodegeneration. However, it remains to be established whether LRP6 is also involved in ischemic brain injury. We used LRP6+/- mice to examine the role of this receptor in the mechanisms of focal cerebral ischemia.Focal cerebral ischemia was induced by transient occlusion of the middle cerebral artery. Motor deficits and infarct volume were assessed 3 days later. Glycogen-synthase-kinase-3? (GSK-3?) phosphorylation was examined by Western blotting with phosphospecific antibodies, and the mitochondrial membrane potential changes induced by Ca2+ were also assessed.LRP6+/- mice have larger stroke and more severe motor deficits, effects that were independent of intraischemic cerebral blood flow, vascular factors, or cytosolic ?-catenin levels. Rather, LRP6 haploinsufficiency increased the activating phosphorylation and decreased the inhibitory phosphorylation of GSK-3?, a kinase involved in proinflammatory signaling and mitochondrial dysfunction. Accordingly, postischemic inflammatory gene expression was enhanced in LRP6+/- mice. Furthermore, the association of mitochondria with activated GSK-3? was increased in LRP6+/- mice, resulting in a reduction in the Ca2+ handling ability of mitochondria. The mitochondrial dysfunction was reversed by pharmacological inhibition of GSK-3?.LRP6 activates an endogenous neuroprotective pathway that acts independently of ?-catenin by controlling GSK-3? activity and preventing its deleterious mitochondrial and proinflammatory effects. The findings raise the possibility that emerging treatment strategies for diseases attributable to LRP6 loss-of-function mutations could also lead to new therapeutic avenues for ischemic stroke.

SUBMITTER: Abe T

PROVIDER: S-EPMC3933931 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Lipoprotein receptor-related protein-6 protects the brain from ischemic injury.

Abe Takato T Zhou Ping P Jackman Katherine K Capone Carmen C Casolla Barbara B Hochrainer Karin K Kahles Timo T Ross Margaret Elizabeth ME Anrather Josef J Iadecola Costantino C

Stroke 20130606 8

<h4>Background and purpose</h4>Loss-of-function mutations of the lipoprotein receptor-related protein-6 (LRP6), a coreceptor in the Wingless-related integration site-β-catenin prosurvival pathway, have been implicated in myocardial ischemia and neurodegeneration. However, it remains to be established whether LRP6 is also involved in ischemic brain injury. We used LRP6+/- mice to examine the role of this receptor in the mechanisms of focal cerebral ischemia.<h4>Methods</h4>Focal cerebral ischemia ...[more]

PMID: 23743975

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Project description:BackgroundNeuroinflammation and immune responses occurring minutes to hours after stroke are associated with brain injury after acute ischemic stroke (AIS). PPARγ coactivator-1α (PGC-1α), as a master coregulator of gene expression in mitochondrial biogenesis, was found to be transiently upregulated in microglia after AIS. However, the role of microglial PGC-1α in poststroke immune modulation remains unknown.MethodsPGC-1α expression in microglia from human and mouse brain samples following ischemic stroke was first determined. Subsequently, we employed transgenic mice with microglia-specific overexpression of PGC-1α for middle cerebral artery occlusion (MCAO). The morphology and gene expression profile of microglia with PGC-1α overexpression were evaluated. Downstream inflammatory cytokine production and NLRP3 activation were also determined. ChIP-Seq analysis was performed to detect PGC-1α-binding sites in microglia. Autophagic and mitophagic activity was further monitored by immunofluorescence staining. Unc-51-like autophagy activating kinase 1 (ULK1) expression was evaluated under the PGC-1α interaction with ERRα. Finally, pharmacological inhibition and genomic knockdown of ULK1 were performed to estimate the role of ULK1 in mediating mitophagic activity after ischemic stroke.ResultsPGC-1α expression was shortly increased after ischemic stroke, not only in human brain samples but also in mouse brain samples. Microglia-specific PGC-1α overexpressing mice exhibited significantly decreased neurologic deficits after ischemic injury, with reduced NLRP3 activation and proinflammatory cytokine production. ChIP-Seq analysis and KEGG pathway analysis revealed that mitophagy was significantly enhanced. PGC-1α significantly promoted autophagic flux and induced autolysosome formation. More specifically, the autophagic clearance of mitochondria was enhanced by PGC-1α regulation, indicating the important role of mitophagy. Pharmacological inhibition or knockdown of ULK1 expression impaired autophagic/mitophagic activity, thus abolishing the neuroprotective effects of PGC-1α.ConclusionsMechanistically, in AIS, PGC-1α promotes autophagy and mitophagy through ULK1 and reduces NLRP3 activation. Our findings indicate that microglial PGC-1α may be a promising therapeutic target for AIS.

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Lipoprotein receptor-related protein-6 protects the brain from ischemic injury.

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Lipoprotein receptor-related protein-6 protects the brain from ischemic injury.

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