title: Neuronal low-density lipoprotein receptor-related protein 1 (LRP1) enhances the anti-apoptotic effect of intravenous immunoglobulin (IVIg) in ischemic stroke.
abstract: The low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional and multi-ligand endocytic receptor abundantly expressed in neurons. Intravenous immunoglobulin (IVIg) is a purified preparation of plasma-derived human immunoglobulin used for the treatment of several neurological inflammatory disorders, and proposed for the treatment of stroke for its potent neuroprotective effects. LRP1 has been shown to be involved in the transcytosis of IVIg, and IVIg-LRP1 interaction leads to LRP1 tyrosine phosphorylation, which may contribute to the anti-inflammatory effects of IVIg. However, the question remains whether IVIg could induce its neuroprotective effects via LRP1 in neurons under ischemic stroke conditions. In cultured neurons and in a transient ischemic mouse model, ischemia decrease LRP1 levels and phosphorylation, and IVIg blocks these effects. In ischemic neurons, LRP1 antagonism by receptor associated protein (RAP) enhances the activation of pro-death signaling pathways such as nuclear factor-kappa B (NF-κB), mitogen-activated protein kinases (MAPKs), and caspase-3, and IVIg reduces these effects. When applied to ischemic neuronal cultures, RAP induces a dramatic drop in Akt activation, and IVIg reverses this effect, as it does with the decrease in Bcl-2 levels caused by ischemic injury in the presence of RAP. Altogether, these results show evidence of LRP1 expression and activity modulation by IVIg, and support the role of LRP1 as a partner of IVIg in the execution of its neuroprotective effects.
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Block MD9, 2 Medical Drive #04-01, Singapore 117597, Singapore; School of Biomedical Sciences, The University of Queensland, Brisbane, Australia.
authors.forename: Ker Zhing
authors.initials: KZ
authors.lastname: Lok
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane 4072, QLD, Australia. Electronic address: s.manzanero@uq.edu.au.
authors.forename: Silvia
authors.initials: S
authors.lastname: Manzanero
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Block MD9, 2 Medical Drive #04-01, Singapore 117597, Singapore; School of Biomedical Sciences, The University of Queensland, Brisbane, Australia; School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea. Electronic address: phstva@nus.edu.sg.
authors.forename: Thiruma V
authors.initials: TV
authors.lastname: Arumugam
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002545:Brain Ischemia / Q000150:complications / Q000378:metabolism*; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000008:administration & dosage*; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D010766:Phosphorylation; D061251:Primary Cell Culture; D011973:Receptors, LDL / Q000378:metabolism*; D020521:Stroke / Q000150:complications / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D016756:Immunoglobulins, Intravenous; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D018696:Neuroprotective Agents; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins
keywords: Apoptosis; IVIg; Ischemia; LRP1; MAPK; Neuroprotection