title: Lipoprotein receptor-related protein-6 protects the brain from ischemic injury.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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-3β (GSK-3β) phosphorylation was examined by Western blotting with phosphospecific antibodies, and the mitochondrial membrane potential changes induced by Ca2+ were also assessed.
  
  
  RESULTS
  LRP6+/- mice have larger stroke and more severe motor deficits, effects that were independent of intraischemic cerebral blood flow, vascular factors, or cytosolic β-catenin levels. Rather, LRP6 haploinsufficiency increased the activating phosphorylation and decreased the inhibitory phosphorylation of GSK-3β, 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-3β 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-3β.
  
  
  CONCLUSIONS
  LRP6 activates an endogenous neuroprotective pathway that acts independently of β-catenin by controlling GSK-3β 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.
authors.affiliation: Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY.
authors.forename: Takato
authors.initials: T
authors.lastname: Abe
authors.affiliation: Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
authors.affiliation: Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY.
authors.forename: Katherine
authors.initials: K
authors.lastname: Jackman
authors.affiliation: Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY.
authors.forename: Carmen
authors.initials: C
authors.lastname: Capone
authors.affiliation: Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY.
authors.forename: Barbara
authors.initials: B
authors.lastname: Casolla
authors.affiliation: Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY.
authors.forename: Karin
authors.initials: K
authors.lastname: Hochrainer
authors.affiliation: Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY.
authors.forename: Timo
authors.initials: T
authors.lastname: Kahles
authors.affiliation: Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY.
authors.forename: Margaret Elizabeth
authors.initials: ME
authors.lastname: Ross
authors.affiliation: Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY.
authors.forename: Josef
authors.initials: J
authors.lastname: Anrather
authors.affiliation: Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY.
authors.forename: Costantino
authors.initials: C
authors.lastname: Iadecola
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D002545:Brain Ischemia / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D008928:Mitochondria / Q000235:genetics; D009043:Motor Activity / Q000235:genetics; D010766:Phosphorylation / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism / Q000502:physiology
chemical_list: D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: Wnt signaling pathway; cerebral ischemia; glycogen-synthase-kinase-3; mitochondria; stroke