Allopregnanolone Promotes Regeneration and Reduces β-Amyloid Burden in a Preclinical Model of Alzheimer's Disease

Abstract

Previously, we demonstrated that allopregnanolone (APα) promoted proliferation of rodent and human neural progenitor cells in vitro. Further, we demonstrated that APα promoted neurogenesis in the hippocampal subgranular zone (SGZ) and reversed learning and memory deficits in the male triple transgenic mouse model of Alzheimer's (3xTgAD). In the current study, we determined the efficacy of APα to promote the survival of newly generated neural cells while simultaneously reducing Alzheimer's disease (AD) pathology in the 3xTgAD male mouse model. Comparative analyses between three different APα treatment regimens indicated that APα administered 1/week for 6 months was maximally efficacious for simultaneous promotion of neurogenesis and survival of newly generated cells and reduction of AD pathology. We further investigated the efficacy of APα to impact Aβ burden. Treatment was initiated either prior to or post intraneuronal Aβ accumulation. Results indicated that APα administered 1/week for 6 months significantly increased survival of newly generated neurons and simultaneously reduced Aβ pathology with greatest efficacy in the pre-pathology treatment group. APα significantly reduced Aβ generation in hippocampus, cortex, and amygdala, which was paralleled by decreased expression of Aβ-binding-alcohol-dehydrogenase. In addition, APα significantly reduced microglia activation as indicated by reduced expression of OX42 while increasing CNPase, an oligodendrocyte myelin marker. Mechanistic analyses indicated that pre-pathology treatment with APα increased expression of liver-X-receptor, pregnane-X-receptor, and 3-hydroxy-3-methyl-glutaryl-CoA-reductase (HMG-CoA-R), three proteins that regulate cholesterol homeostasis and clearance from brain. Together these findings provide preclinical evidence for the optimal treatment regimen of APα to achieve efficacy as a disease modifying therapeutic to promote regeneration while simultaneously decreasing the pathology associated with Alzheimer's disease.

Kallikrein‐8 inhibition attenuates Alzheimer's disease pathology in mice

“…The other potential KLK8 substrate candidate, Srd5a1 participates in the biosynthesis of allopregnanolone which is a neurosteroid with anxiolytic properties [40]. AD patients have reduced allopregnanolone levels [41], whereas allopregnanolone administration improves cognitive performance and promotes hippocampal neurogenesis in the 3xTg AD mouse model [42,43]. Further investigations should verify the effects of anti-KLK8 treatment on fibronectin as well as Srd5a1-mediated allopregnanolone biosynthesis.…”

Advances in the Understanding of the Gabaergic Neurobiology of FMR1 Expanded Alleles Leading to Targeted Treatments for Fragile X Spectrum Disorder

“…Preliminary data demonstrated in an AD mouse model and human progenitor cells that allopregnanolone improved neuronal proliferation [114], reversed neurogenic and cognitive deficits [115], promoted regeneration and reduced beta-amyloid burden [116], restored hippocampal dependent learning, and improved memory and survival [108]. In addition, allopregnanolone is reduced in the prefrontal and temporal cortex in AD.…”

Frontiers in therapeutic development of allopregnanolone for Alzheimer’s disease and other neurological disorders

“…In addition to the mechanism of action whereby Allo induces neurogenesis (Brinton, 2013), Allo regulates cholesterol homeostasis via mechanisms that increases liver-X-receptor (LXR) and pregnane-X-receptor (PXR; Chen et al, 2011). LXR is a nuclear hormone receptor abundant in the brain, primarily expressed in glial cells and acts as a molecular sensor of cholesterol levels and initiates cholesterol clearance (Whitney et al, 2002; Jakobsson et al, 2012).…”