Liver X Receptor activation protects Huntington’s disease knock-in mice from behavioral and neuropathological impairments

Cholesterol homeostasis is crucial for brain function and is disrupted in neurodegenerative diseases such as Huntington’s disease (HD). Restoring brain cholesterol homeostasis has strong therapeutic potential, but the best options to this end have remained elusive. As Liver X Receptors (LXRα/β) control cholesterol homeostasis, we investigated the effect of LXR chronic activation using T0901317 in HD mice to evaluate its neuroprotective effect. T0901317 improved recognition memory and reduced social and depressive-like deficits, the early signs of the disease in persons with HD. Deep RNA-sequencing analysis revealed that these improvements are associated with a corrected expression of striatal neuron identity genes, and of genes linked to cholesterol metabolism and neurotransmission, in the striatum and hippocampus. Strikingly, neuronal Bdnf expression was rescued in the dentate gyrus, along with a restoration of adult neurogenesis. However, the long-term use of T0901317 is hindered by liver toxicity driven by LXRα activation. To overcome this limitation, we investigated the effects of a steroidal, semi-synthetic LXR ligand (PFM014) in an HD mouse model. In silico modeling provided molecular evidence supporting PFM014 as a brain-selective LXRβ agonist which is a key challenge in the development of LXR-targeted therapies. Remarkably, PFM014 treatment in HD mice produced robust neuroprotective effects and significant cognitive improvement. Collectively, these findings highlight selective LXRβ activation as a promising and innovative therapeutic avenue for Huntington’s disease.