Ganaxolone Reverses the Effect of Amyloid β-Induced Neurotoxicity by Regulating the Liver X Receptor Expression in APP Transfected SH-SY5Y Cells and Murine Model of Alzheimer's Disease

Inhibiting beta-amyloid aggregation and enhancing its clearance are the key strategies in Alzheimer's disease (AD) treatment. Liver X receptors (LXRs) plays a crucial role in cholesterol homeostasis and inflammation, and their activation can clear A beta aggregates in AD. Allopregnanolone, a neurosteroid, positively influences AD through LXR regulation, while ganaxolone, its synthetic analog, is known for its neuroprotective properties. This study explores the effect of ganaxolone on LXR activation and regulation of genes involved in mitigating A beta toxicity and tauopathy in SH-SY5Y cells transfected with APP695 Swe/Ind plasmid and an A beta 1-42 induced AD mouse model. Molecular docking stimulations indicated ganaxolone's binding and interaction with LXR beta. Subsequently, transfected neuronal cells exhibited increased mRNA levels of APP, TNF-alpha and IL-1 beta, decreased cell viability, reduced MMP and altered protein expression of A beta, LXR, BCL-2, APOE, ABCA1, along with increased levels of mROS, Bax, and caspase 3 activity. Ganaxolone treatment significantly abrogated A beta-induced effect in transfected neuronal cells by enhancing LXR beta expression, inducing LXR:RXR colocalization, thereby increasing APOE and ABCA1 expression. It also decreased tau mRNA levels in transfected cells. Importantly, in AD mice, ganaxolone ameliorated cognitive impairment, reduced A beta toxicity, tau levels, and neuroinflammatory markers, restored mitochondrial function, and decreased neuronal apoptosis. Taken together, these novel results highlight the central role of LXR in mediating A beta-induced toxicity and provide preclinical evidence for ganaxolone as a potential agent to reduce toxicity in an LXR-dependent manner. This may serve as a promising treatment strategy to slow or prevent neurodegeneration in AD patients.image