Neuroregenerative mechanisms of allopregnanolone in Alzheimer's disease

The proliferative pool and regenerative potential of neural stem cells diminishes with age, a phenomenon that may be exacerbated in prodromal and mild Alzheimer's disease (AD) brains. In parallel, the neuroactive progesterone metabolite, allopregnanolone (AP_α), along with a host of other factors, is decreased in the AD brain. Results of preclinical analyses demonstrate that AP_α is a potent inducer of neural progenitor proliferation of both rodent and human derived neural progenitor cells in vitro. In vivo,AP_α significantly increased neurogenesis within the subgranular zone of the dentate gyrus and subventricular zone of the 3×TgAD mouse model. Functionally, AP_α reversed the learning and memory deficits of 3×TgAD mice prior to and following the onset of AD pathology and was comparably efficacious in aged normal mice. In addition to inducing regenerative responses in mouse models of AD, AP_α significantly reduced beta-amyloid burden, beta-amyloid binding alcohol dehydrogenase load, and microglial activation. In parallel, AP_α increased markers of white matter generation and cholesterol homeostasis. Analyses to determine the optimal treatment regimen in the 3×TgAD mouse brain indicated that a treatment regimen of AP_α once per week was optimal for both inducing neurogenesis and reducing AD pathology. Pharma-cokinetic analyses indicated that AP_α is rapidly increased in both plasma and brain following a single dose. AP_α is most efficacious when administered once per week which will contribute to its margin of safety. Further, analyses in both animals and humans have provided parameters for safe AP_α dosage exposure in humans. From a translational perspective, AP_α is a small molecular weight, blood brain barrier penetrant molecule with substantial preclinical efficacy data as a potential Alzheimer's therapeutic with existing safety data in animals and humans.To our knowledge, AP_α is the only small molecule that both promotes neural progenitor regeneration in brain and simultaneously reduces AD pathology burden.