Therapeutic potential of neurogenesis for prevention and recovery from Alzheimer's disease: allopregnanolone as a proof of concept neurogenic agent.
A major challenge not yet addressed by current therapeutic interventions for Alzheimer's disease (AD) is the regeneration of lost neurons and neural circuitry to restore cognitive function. Therapies that lead to cessation of the degenerative process still leave the brain riddled with deteriorated neural circuits and reduced neuron number. The discovery of neurogenesis in the adult brain and the regenerative potential of neural stem cells holds the promise for restoration of neural populations and regeneration of neural circuits necessary for cerebral function. While the regenerative potential of neural stem cells is great, so too is the challenge of delivering neural stem cells to the brain. Basic science analyses and human trials indicate that constituents of microenvironments within the brain determine the neurogenic potential, phenotypic differentiation of neural stem cells and magnitude of the neural stem cell pool. Multiple analyses have documented that dentate neurogenesis is regulated by multiple growth factors which are abundant during development and which dramatically decline with age. While the cause(s) of age-associated decline in neurogenesis remains to be fully determined, loss in growth factors, FGF-2, IGF-1 and VEGF, in the microenvironment of the subgranular zone (SGZ) are prime contributors to the reduced neurogenic potential. The decline in dentate neurogenesis can be observed as early as middle age. In the aged and AD brain, both the pool of neural stem cells and their proliferative potential are markedly diminished. In parallel, the level of potential regenerative factors is diminished in the brains of Alzheimer's patients compared to age-matched controls. Our efforts have been directed towards discovery and development of small, blood brain barrier penetrant molecules to promote endogenous proliferation of neural stem cells within the brain. These endeavors have led to the discovery that the neurosteroid alloprognanolone (APalpha) is a potent and highly efficacious proliferative agent in vitro and in vivo of both rodent and human neural stem cells. Results of our in vitro studies coupled with our more recent analyses in the triple transgenic mouse model of AD suggest that APalpha is a promising strategy for promoting neurogenesis in the aged brain and potentially for restoration of neuronal populations in brains recovering from neurodegenerative disease or injury. A brief overview of issues impacting the therapeutic potential of neurogenesis and the factors used to promote neurogenesis in the aging and degenerating brain is presented. Also included is a review of our current research into the neurogenic potential of the small molecule, blood brain barrier penetrating, neurosteroid allopregnanolone (APalpha).
Brinton
Roberta Diaz
RD
Department of Molecular Pharmacology and Toxicology and Program in Neuroscience, Pharmaceutical Science Center, 1985 Zonal Avenue, University of Southern California, Los Angeles, CA 90033, USA. rbrinton@hsc.usc.edu
Wang
Jun Ming
JM
D000375:Aging / Q000502:physiology; D000544:Alzheimer Disease / Q000378:metabolism / Q000628:therapy*; D000818:Animals; D001921:Brain / Q000166:cytology / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009416:Nerve Regeneration / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D011280:Pregnanolone / Q000502:physiology* / Q000627:therapeutic use; D033581:Stem Cell Transplantation / Q000379:methods; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism
D011280:Pregnanolone