Garcinoic acid prevents β-amyloid (Aβ) deposition in the mouse brain

Rita Marinelli,Pierangelo Torquato,Desirée Bartolini,Cristina Mas-Bargues,Guido Bellezza,Antimo Gioiello,Consuelo Borras,Antonella De Luca,Francesca Fallarino,Bartolomeo Sebastiani,Sridhar Mani,Angelo Sidoni,Jose Viña,Manuela Leri,Monica Bucciantini,Pamela Nardiello,Fiorella Casamenti,Francesco Galli

doi:10.1074/jbc.ra120.013303

Abstract

Garcinoic acid (GA or δ-T3-13'COOH), is a natural vitamin E metabolite that has preliminarily been identified as a modulator of nuclear receptors involved in β-amyloid (Aβ) metabolism and progression of Alzheimer's disease (AD). In this study, we investigated GA's effects on Aβ oligomer formation and deposition. Specifically, we compared them with those of other vitamin E analogs and the soy isoflavone genistein, a natural agonist of peroxisome proliferator–activated receptor γ (PPARγ) that has therapeutic potential for managing AD. GA significantly reduced Aβ aggregation and accumulation in mouse cortical astrocytes. Similarly to genistein, GA up-regulated PPARγ expression and apolipoprotein E (ApoE) efflux in these cells with an efficacy that was comparable with that of its metabolic precursor δ-tocotrienol and higher than those of α-tocopherol metabolites. Unlike for genistein and the other vitamin E compounds, the GA-induced restoration of ApoE efflux was not affected by pharmacological inhibition of PPARγ activity, and specific activation of pregnane X receptor (PXR) was observed together with ApoE and multidrug resistance protein 1 (MDR1) membrane transporter up-regulation in both the mouse astrocytes and brain tissue. These effects of GA were associated with reduced Aβ deposition in the brain of TgCRND8 mice, a transgenic AD model. In conclusion, GA holds potential for preventing Aβ oligomerization and deposition in the brain. The mechanistic aspects of GA's properties appear to be distinct from those of other vitamin E metabolites and of genistein.

Highlights

Garcinoic acid (GA or d-T3-13’COOH), is a natural vitamin E metabolite that has preliminarily been identified as a modulator of nuclear receptors involved in b-amyloid (Ab) metabolism and progression of Alzheimer’s disease (AD)
Ab aggregation and metabolism in mouse astrocytes—First, acute toxicity in mouse astrocytes was excluded for all the test compounds (GE, a-TOH, a-long-chain metabolites (LCMs), garcinoic acid (GA), and d-T3) investigated either separate (Fig. S1A and Table S1) or combined with Ab treatment (Fig. S1B, Table S1)
Immunolocalization of Ab1-42 aggregates demonstrated that the pre-treatment with GA and GE reduces the number and dimension of Ab oligomers that interact with the plasmalemma of murine astrocytes (Fig. 2C)

Summary

Introduction

Garcinoic acid (GA or d-T3-13’COOH), is a natural vitamin E metabolite that has preliminarily been identified as a modulator of nuclear receptors involved in b-amyloid (Ab) metabolism and progression of Alzheimer’s disease (AD). Unlike for genistein and the other vitamin E compounds, the GA-induced restoration of ApoE efflux was not affected by pharmacological inhibition of PPARg activity, and specific activation of pregnane X receptor (PXR) was observed together with ApoE and multidrug resistance protein 1 (MDR1) membrane transporter up-regulation in both the mouse astrocytes and brain tissue.

Results

Conclusion