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. 2025 Feb;169(2):e70007.
doi: 10.1111/jnc.70007.

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

Divya  1 , Mohammed Faruq  2 , Sheikh Sana Nazir  1 , Pooja Kaushik  3 , Suhel Parvez  3 , Divya Vohora  1
Affiliations

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

Divya et al. J Neurochem. 2025 Feb.

Abstract

Inhibiting β-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 Aβ 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 Aβ toxicity and tauopathy in SH-SY5Y cells transfected with APP695 Swe/Ind plasmid and an Aβ1-42 induced AD mouse model. Molecular docking stimulations indicated ganaxolone's binding and interaction with LXRβ. Subsequently, transfected neuronal cells exhibited increased mRNA levels of APP, TNF-α and IL-1β, decreased cell viability, reduced MMP and altered protein expression of Aβ, LXR, BCL-2, APOE, ABCA1, along with increased levels of mROS, Bax, and caspase 3 activity. Ganaxolone treatment significantly abrogated Aβ-induced effect in transfected neuronal cells by enhancing LXRβ 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 Aβ 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 Aβ-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.

Keywords: Alzheimer's disease; amyloid‐beta; ganaxolone; liver X receptor; neurosteroid; neurotoxicity.

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