Abstract
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 (APα), along with a host of other factors, is decreased in the AD brain. Results of preclinical analyses demonstrate that APα is a potent inducer of neural progenitor proliferation of both rodent and human derived neural progenitor cells in vitro. In vivo, APα significantly increased neurogenesis within the subgranular zone of the dentate gyrus and subventricular zone of the 3xTgAD mouse model. Functionally, APα reversed the learning and memory deficits of 3xTgAD 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, APα significantly reduced beta-amyloid burden, beta-amyloid binding alcohol dehydrogenase load, and microglial activation. In parallel, APα increased markers of white matter generation and cholesterol homeostasis. Analyses to determine the optimal treatment regimen in the 3xTgAD mouse brain indicated that a treatment regimen of APα once per week was optimal for both inducing neurogenesis and reducing AD pathology. Pharmacokinetic analyses indicated that APα is rapidly increased in both plasma and brain following a single dose. APα 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 APα dosage exposure in humans. From a translational perspective, APα 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, APα is the only small molecule that both promotes neural progenitor regeneration in brain and simultaneously reduces AD pathology burden.
Highlights
Dynamic neural stem-cell proliferation zones apparent in the developing central nervous system are present in the adult brain, primarily restricted to the dentate gyrus subgranular zone (SGZ; Altman and Das, 1965; Cameron et al, 1993; reviewed in Liu and Brinton, 2010) of the hippocampus and the subventricular zone (SVZ) of the lateral ventricle (Altman, 1969; Luskin, 1993; reviewed in Liu and Brinton, 2010)
Together with the dosing frequency, the magnitude of pathology at the start of treatment intervention is critical to therapeutic efficacy
Administration of APα prior to and during the early stages of Alzheimer’s disease (AD) pathology significantly increased the regenerative response in brain while reducing burden of pathology in an AD mouse model
Summary
Dynamic neural stem-cell proliferation zones apparent in the developing central nervous system are present in the adult brain, primarily restricted to the dentate gyrus subgranular zone (SGZ; Altman and Das, 1965; Cameron et al, 1993; reviewed in Liu and Brinton, 2010) of the hippocampus and the subventricular zone (SVZ) of the lateral ventricle (Altman, 1969; Luskin, 1993; reviewed in Liu and Brinton, 2010). Consistent with a calcium-dependent mechanism for neuroproliferation, APα induced a rapid increase in intracellular calcium in hippocampal neurons via a GABAAR-activated L-type calcium channel (Wang and Brinton, 2008). We review here three studies from our laboratory in which a correlation was made between APα-induced neural progenitor cell survival and improved memory function in 3xTgAD mice (Wang et al, 2010; Chen et al, 2011; Singh et al, 2011).
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