The impact of novel Xe delivery on Alzheimer‐related gene regulation

Abstract

AbstractBackgroundEffective treatments for Alzheimer’s disease (AD) are classically designed to canonical disease players (e.g., misfolded proteins, neurodegeneration, and brain inflammation). Importantly, treatments must be able to cross the blood‐brain barrier (BBB) to cause meaningful therapeutic effects. Sufficient evidence has demonstrated that xenon (Xe), a bioactive gas, has profound neuroprotective effects with advantages of rapid diffusion across the BBB into hypoperfused brains without side effects. For chronic use, a long‐term and effective Xe delivery method is needed. Here, we present novel Xe formulations with effective cerebral delivery strategies for extended endogenous neuroprotection and neurorestoration.MethodOrally deliverable Xe cyclodextrin (Xe‐CD) and intravenous deliverable Xe‐liposome were prepared. Xe‐CD was orally administrated in aged (10 months old) ApoE knockout mice fed with high‐fat diet for 6 weeks. The brain and blood amyloid‐β (Aβ) levels were measured by ELISA. To extend therapeutic effects, Xe‐liposomes were intravenously administrated using an intermittent repetitive administration strategy in a rat stroke model. Xe effects on epigenetic regulation were evaluated in this rat stroke model using Whole‐genome bisulfite sequencing (WGBS) and gene pathway enrichment analyses. Neurocognitive recovery was also evaluated.ResultAged (10 months old) ApoE knockout mice fed with high‐fat diet for 6 weeks developed high Ab expression levels in the brain and blood. However, Xe oral administration for 6‐week prevented the high‐fat diet‐induced Aβ elevation. Repetitive intermittent administration of Xe formulations extended the protective effects over time as long‐term memory restoration post stroke was observed. Whole‐genome bisulfite sequencing (WGBS) and gene pathway enrichment analyses revealed enrichment of differential methylation in multiple biologic pathways associated with growth factor response, memory consolidation, synaptic plasticity, and brain aging in the hippocampus. Of interesting, Xe regulated endogenous β‐secretase (BACE1), and low‐density lipoprotein receptor‐related protein 1 (LRP1), both of which are known to be associated with Ab. Xe also regulated memory and age related genes such as Gadd45b, DMNT3a, and HDAC9; and growth factor related genes NTrK2 and NGF. Gadd45b and PFAa also regulate long‐term memory consolidation.ConclusionWe have developed a novel Xe formulation and delivery strategy for long‐term neuroprotection that stabilizes the brain through multiple pathways.