Neuroregenerative Mechanisms of Allopregnanolone in Alzheimer’s Disease

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.

Environmental enrichment attenuates the age-related decline in the mRNA expression of steroidogenic enzymes and reduces the methylation state of the steroid 5α-reductase type 1 gene in the rat hippocampus

“…Particularly, allopregnanolone promotes the proliferation of rodent neural progenitor cells and neuron survival (Wang et al, 2005), inhibits apoptosis in the late gestation fetal brain (Yawno et al, 2009), prevents memory impairment in rats (Escudero et al, 2012) and mice (Singh et al, 2012) and plays a key role in neurodegenerative diseases such as AD (Brinton, 2013;Irwin et al, 2011;Marx et al, 2006;Wang et al, 2008).…”

Analytical challenges for measuring steroid responses to stress, neurodegeneration and injury in the central nervous system

“…However, as in stress disorders and depression, there is evidence for reduced allopregnanolone levels in brain, CSF and plasma. These results gain their pathophysiological significance from the experimental work on the protective and neuroregenerative actions of allopregnanolone [3,161]. Thus, repeated measures revealed reduced serum levels of allopregnanolone in patients with AD when compared to control subjects.…”

Label-free imaging and quantitative chemical analysis of Alzheimer’s disease brain samples with multimodal multiphoton nonlinear optical microspectroscopy

“…5(e)] due to GABA, a neurotransmitter reported as the most prominent feature in AD in many research papers. [5][6][7][30][31][32] This means that GABA is more highly accumulated in the DG in the AD sample than in the normal sample. We also observed higher autofluorescence signals, as shown in Fig.…”

“…This is because considerable GABA, the chemical characteristics of which are responsible for the CH 2 symmetric stretching mode, accumulates as AD progresses. 5,6,[30][31][32] To analyze quantitatively the difference in the CARS spectra of the control and AD brain samples, all the data were normalized by setting the 2845 cm −1 peak equal to 1.0. Figure 6(b) shows the normalized versions of the spectra in Fig.…”