Retinoid X receptor activation promotes re-myelination in a very old triple transgenic mouse model of Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is the main cause of dementia in the world. Studies of human AD brains show abnormalities in the white matter and reduction of myelin and oligodendrocyte markers. It has been proposed that oligodendrocyte progenitor cells (OPCs) present in the adult brain are a potential source for re-myelination, through proliferation and differentiation into mature oligodendrocytes. Bexarotene, a Retinoid X Receptor agonist, has been demonstrated to reverse behavioral deficits and to improved synaptic transmission and plasticity in murine models of AD, which was associated with the reduction of soluble Aβ peptides. In the present study, we analyzed changes in the expression of oligodendrocyte lineage markers following oral administration of Bexarotene in a very old (24-month-old) triple transgenic mouse model of AD (3xTg-AD), for which early demyelination changes have been previously described. Bexarotene increased the expression of OPCs and intermediate oligodendrocyte progenitors (Olig2+ and O4+), and increased the number of mitotic (O4+) and myelinating mature (MBP+) oligodendrocytes. We clearly show that Bexarotene promotes re-myelination which might be important for the previously observed cognitive improvement of 3xTg-AD mice treated with this drug.