title: Rescuing effects of RXR agonist bexarotene on aging-related synapse loss depend on neuronal LRP1.
abstract: Apolipoprotein E (apoE) plays a critical role in maintaining synaptic integrity by transporting cholesterol to neurons through the low-density lipoprotein receptor related protein-1 (LRP1). Bexarotene, a retinoid X receptor (RXR) agonist, has been reported to have potential beneficial effects on cognition by increasing brain apoE levels and lipidation. To investigate the effects of bexarotene on aging-related synapse loss and the contribution of neuronal LRP1 to the pathway, forebrain neuron-specific LRP1 knockout (nLrp1(-/-)) and littermate control mice were administered with bexarotene-formulated diet (100mg/kg/day) or control diet at the age of 20-24 months for 8 weeks. Upon bexarotene treatment, levels of brain apoE and ATP-binding cassette sub-family A member 1 (ABCA1) were significantly increased in both mice. While levels of PSD95, glutamate receptor 1 (GluR1), and N-methyl-d-aspartate receptor NR1 subunit (NR1), which are key postsynaptic proteins that regulate synaptic plasticity, were decreased with aging, they were restored by bexarotene treatment in the brains of control but not nLrp1(-/-) mice. These results indicate that the beneficial effects of bexarotene on synaptic integrity depend on the presence of neuronal LRP1. However, we also found that bexarotene treatment led to the activation of glial cells, weight loss and hepatomegaly, which are likely due to hepatic failure. Taken together, our results demonstrate that apoE-targeted treatment through the RXR pathway has a potential beneficial effect on synapses during aging; however, the therapeutic application of bexarotene requires extreme caution due to its toxic side effects.
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Masaya
authors.initials: M
authors.lastname: Tachibana
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Shinohara
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yamazaki
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Chia-Chen
authors.initials: CC
authors.lastname: Liu
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Rogers
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Electronic address: bu.guojun@mayo.edu.
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Electronic address: kanekiyo.takahisa@mayo.edu.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Kanekiyo
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000375:Aging / Q000187:drug effects*; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D000077610:Bexarotene; D001921:Brain / Q000166:cytology* / Q000187:drug effects; D002135:Calcium-Binding Proteins / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D005786:Gene Expression Regulation / Q000187:drug effects; D051528:Guanylate Kinases / Q000378:metabolism; D008107:Liver Diseases / Q000209:etiology; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D047488:Retinoid X Receptors / Q000819:agonists*; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage*; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics
chemical_list: D064286:ATP Binding Cassette Transporter 1; D001057:Apolipoproteins E; D000077610:Bexarotene; D002135:Calcium-Binding Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D000076122:Disks Large Homolog 4 Protein; D051528:Guanylate Kinases; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D011973:Receptors, LDL; D016194:Receptors, N-Methyl-D-Aspartate; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D025521:Tumor Suppressor Proteins; C577833:Abca1 protein, mouse; C491049:Aif1 protein, mouse; C501447:Dlg4 protein, mouse; C121673:Gprin1 protein, mouse; C486645:Lrp1 protein, mouse
keywords: Aging; Bexarotene; LRP1; Nuclear receptor; RXR agonist; Retinoid; Synapse; apoE