Endocrine Abstracts

Allopregnanolone (APα), a neurosteroid, significantly increased proliferation of rodent and human neural progenitor cells in vitro via GABA receptor channel and L-type channel mechanisms that activated the cell cycle. We subsequently investigated the efficacy of APα to promote neurogenesis in the hippocampal subgranular zone (SGZ), to reverse learning and memory deficits in the 3 month-old male triple transgenic mouse model of Alzheimer’s (3xTgAD). APα significantly increased BrdU⁺ cells in SGZ in 3xTgAD mice and restored SGZ proliferation to normal magnitude.Further, APα reversed the cognitive deficits to restore learning and memory performance to the level of normal non-Tg mice. In 3xTgAD mice, APα-induced survival of neural progenitors was significantly correlated with APα -induced memory performance. We then determined efficacy of APα to restore neural progenitor cell survival and cognition subsequent to AD pathology in male 3xTgAD and nonTg mice. APα significantly increased survival of BrdU⁺ cells and cognition in 3xTgAD mice in the presence of intraneuronal Aβ whereas APα was ineffective subsequent to development of extraneuronal Aβ plaques. Restoration of cognition was maximal by the first day and sustained throughout behavioral training. Learning and memory function in APα -treated 3xTgAD mice was 100% greater than vehicle-treated and comparable to maximal normal nonTg performance. In aged 15-month-old nonTg mice, APα significantly increased survival of BrdU⁺ cells and cognition. Because long-term therapeutic clinical efficacy will be modified by progression of AD pathology, we determined the efficacy of APα to promote neurogenesis while simultaneously reducing Alzheimer’s disease (AD) pathology. Treatment was initiated either prior to or post intraneuronal Aβ accumulation. Results indicated that APα significantly increased survival of newly generated neurons and simultaneously reduced Aβ pathology with greatest efficacy in the pre-pathology treatment group. APα also significantly reduced microglia activation while increasing CNPase, an oligodendrocyte myelin marker. These results provide preclinical evidence that APα promoted survival of newly generated cells and restored cognitive performance in the pre-plaque phase of AD pathology and in late-stage normal aging. Supported by NIA to RDB.