Rescuing effects of RXR agonist bexarotene on aging-related synapse loss depend on neuronal LRP1

Masaya Tachibana, Mitsuru Shinohara, Yu Yamazaki, Chia Chen Liu, Justin Rogers, Guojun Bu, Takahisa Kanekiyo

Research output: Contribution to journalArticle

32 Scopus citations

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 20-24months for 8weeks. 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.

Original languageEnglish (US)
Pages (from-to)1-9
Number of pages9
JournalExperimental Neurology
Volume277
DOIs
StatePublished - Mar 1 2016

Keywords

  • Aging
  • ApoE
  • Bexarotene
  • LRP1
  • Nuclear receptor
  • RXR agonist
  • Retinoid
  • Synapse

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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