Regenerative potential of allopregnanolone

The neuroendocrine status of the brain has been linked to the quality of the aging process, to the risk of Alzheimer's disease and to progression of neurodegenerative pathology. Data from multiple levels of analysis ranging from in vitro cellular models to in vivo animal models to clinical investigations indicate that the decline of neurosteroids play a key role in successful aging and prevention of neurodegenerative disease Alzheimer's. Among the neurosteroids in decline during aging is allopregnanolone (APalpha, a metabolite of progesterone, which is reduced in the serum, plasma and brain of aged vs. young subjects. Further, Alzheimer's disease (AD) victims exhibit an even greater reduction in plasma and brain levels of APalpha relative to age-matched neurologically normal controls. Our earlier work has shown that APalpha is a neurogenic agent for rodent hippocampal neural progenitors and for human neural progenitor cells derived from the cerebral cortex. Our ongoing research seeks to determine the neurogenic potential of APalpha in the triple transgenic mouse model of Alzheimer's disease (3 x TgAD) as AD related pathology progresses from imperceptible to mild to severe. Initial analyses suggest that APalpha may maintain the regenerative ability of the brain, modify progression of AD related pathology and reverse learning and memory deficits in 3 x TgAD mice. This review summarizes current APalpha research in different animal models, neural progenitor regeneration within a degenerative milieu and the challenge for developing neuroregenerative therapeutics.