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 (100 mg/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.

LXR Regulation of Brain Cholesterol: From Development to Disease

“…Previous evidence has suggested that RXR and its heterodimer partners are able to regulate the transcription of neuronal genes important for neurogenesis and neurite extension [67–70], synaptic function [71], and neuronal survival [1]. A recent study from Sandoval-Hernandez et al reports that treatment of 3xTg-AD mice with LXR agonist GW3965 increases proliferation of neural precursors in the subgranular zone and rescues Aβ-induced deficits in long-term potentiation (LTP) in a protein-synthesis dependent manner [72].…”

Apolipoprotein E as a Therapeutic Target in Alzheimer’s Disease: A Review of Basic Research and Clinical Evidence

“…Bexarotene significantly slowed cognitive decline in an amyloid mouse model expressing human APOE ε 3 and APOE ε4 [121], and reversed the APOE ε4-induced cognitive and neuronal impairments in mice without amyloid background [99]. Age-dependent loss of synaptic proteins is also restored by bexarotene [102]. However, there are conflicting reports regarding the effects of bexarotene treatment on amyloid pathology in mouse models [101, 103, 105, 106, 121].…”

“…However, there are conflicting reports regarding the effects of bexarotene treatment on amyloid pathology in mouse models [101, 103, 105, 106, 121]. In addition, bexarotene-induced adverse side effects including hepatic failure have been reported [102, 104]. Furthermore, in a clinical study, four weeks of bexarotene treatment in AD patients did not reduce brain amyloid as measured by PET scans, but the sample size was notably small (ClinicalTrials.gov identifier NCT01782742) [122].…”

Therapeutic targeting of nuclear receptors, liver X and retinoid X receptors, for Alzheimer's disease

“…In this regard, it is important to emphasize that bexarotene treatment attenuated neuronal loss in the subiculum and cortex in 5xFAD mice, which correlated with significant increases in the levels of post‐synaptic marker PSD95 and the presynaptic marker synaptophysin (Mariani et al, ). Tachibana et al presented the ability of bexarotene to restore the levels of post‐synaptic proteins (PSD95, GluR1, and NR1) which were observed to be diminished with age and important in synaptic plasticity (Tachibana et al, ). RXR agonists were also shown to have therapeutic potential in reversing the age‐associated decreases in myelin debris removal and remyelination (Natrajan et al, ).…”

“…Tachibana et al presented the ability of bexarotene to restore the levels of post-synaptic proteins (PSD95, GluR1, and NR1) which were observed to be diminished with age and important in synaptic plasticity (Tachibana et al, 2016). RXR agonists were also shown to have therapeutic potential in reversing the age-associated decreases in myelin debris removal and remyelination (Natrajan et al, 2015).…”