Abstract
Previous studies demonstrated that the endogenous neurosteroid allopregnanolone (Allo) promotes regeneration of rodent and human neural progenitor/neural stem cells (NSCs) in vitro and in vivo, and restores neurogenesis and cognitive function in the male triple transgenic mouse model of Alzheimer's disease (3xTgAD). In this study, we investigated Allo regulation of neuronal differentiation of adult mouse neural stem cells from both sexes. Outcomes indicated that the age-dependent shift from neuronal to glial differentiation was accelerated and magnified in 3xTgAD adult NSCs compared to that in age-matched non-Tg NSCs. Coincident with the decline in neuronal differentiation, the number of immature neurons declined earlier in 3xTgAD mice, which was consistent with observations in the aged Alzheimer's human brain. Allo treatment restored the neuron/astrocyte ratio derived from adult 3xTgAD NSCs and increased both NSC proliferation and differentiation in the 3xTgAD brain. Allo treatment also significantly increased expression of Olig2, an oligodendrocyte precursor cell marker, as well as Olig2-positive cells in the corpus callosum of 3xTgAD mice. Increased neuronal and oligodendrocyte differentiation was paralleled by an increase in the expression levels of insulin-like growth factor-1 (IGF-1) and IGF-1 receptor (IGF-1R). Collectively, these findings are consistent with Allo acting as a pleiotropic therapeutic to promote regeneration of gray and white matter in the Alzheimer's brain.