Allopregnanolone Promotes Regeneration and Reduces β-Amyloid Burden in a Preclinical Model of Alzheimer's Disease

Previously, we demonstrated that allopregnanolone (AP alpha) promoted proliferation of rodent and human neural progenitor cells in vitro. Further, we demonstrated that AP alpha promoted neurogenesis in the hippocampal subgranular zone (SGZ) and reversed learning and memory deficits in the male triple transgenic mouse model of Alzheimer's (3xTgAD). In the current study, we determined the efficacy of AP alpha to promote the survival of newly generated neural cells while simultaneously reducing Alzheimer's disease (AD) pathology in the 3xTgAD male mouse model. Comparative analyses between three different AP alpha treatment regimens indicated that AP alpha administered 1/week for 6 months was maximally efficacious for simultaneous promotion of neurogenesis and survival of newly generated cells and reduction of AD pathology. We further investigated the efficacy of AP alpha to impact A beta burden. Treatment was initiated either prior to or post intraneuronal A beta accumulation. Results indicated that AP alpha administered 1/week for 6 months significantly increased survival of newly generated neurons and simultaneously reduced A beta pathology with greatest efficacy in the pre-pathology treatment group. AP alpha significantly reduced A beta generation in hippocampus, cortex, and amygdala, which was paralleled by decreased expression of A beta-binding-alcohol-dehydrogenase. In addition, AP alpha significantly reduced microglia activation as indicated by reduced expression of OX42 while increasing CNPase, an oligodendrocyte myelin marker. Mechanistic analyses indicated that pre-pathology treatment with AP alpha increased expression of liver-X-receptor, pregnane-X-receptor, and 3-hydroxy-3-methyl-glutaryl-CoA-reductase (HMG-CoA-R), three proteins that regulate cholesterol homeostasis and clearance from brain. Together these findings provide preclinical evidence for the optimal treatment regimen of AP alpha to achieve efficacy as a disease modifying therapeutic to promote regeneration while simultaneously decreasing the pathology associated with Alzheimer's disease.