Ask about this productRelated genes to: CYP46A1 Blocking Peptide
- Gene:
- CYP46A1 NIH gene
- Name:
- cytochrome P450 family 46 subfamily A member 1
- Previous symbol:
- CYP46
- Synonyms:
- -
- Chromosome:
- 14q32.2
- Locus Type:
- gene with protein product
- Date approved:
- 1999-08-20
- Date modifiied:
- 2015-12-09
Related products to: CYP46A1 Blocking Peptide
Related articles to: CYP46A1 Blocking Peptide
- Alzheimer's disease (AD) is the most prevalent form of dementia and is characterized by abnormal aggregation of β-amyloid (Aβ) peptides, tau proteins, and neuroinflammation in the central nervous system (CNS). While most AD research has focused on the brain, the molecular pathology of the spinal cord remains poorly understood. In this study, we investigated amyloid pathology, neurodegeneration, neuroinflammation, and cholesterol metabolism across distinct regions of the spinal cord and examined sex-specific differences using a model of AD, 5xFAD mice. Our data reveal that Aβ accumulation was restricted to the cervical spinal cord at 3 months but was evident in all areas of the spinal cord by 9 months, with similar patterns in both female and male animals. Despite this early and progressive Aβ deposition, no significant neuronal loss was observed in the ventral horn of the cervical spinal cord in either sex at 3 or 9 months of age. In contrast, there was a significant positive correlation between Aβ deposition and Iba1+ cell density in the spinal cord of 5xFAD mice. The number of Iba1+ cells in both the grey and white matter was significantly increased in female and male 5xFAD mice compared with age-matched wild-type (WT) littermates at 9 months of age. Astrocytic responses, however, were sex-specific: female, but not male, 5xFAD mice exhibited a significant increase in GFAP+ astrocytes in the grey matter of the thoracic and lumber spinal cord at 9 months compared with 3 months and relative to age-matched WT controls in the cervical and thoracic spinal cord. Furthermore, GFAP+ area in the thoracic spinal cord was significantly higher in female 9-month-old 5xFAD mice compared with their male counterparts, indicating a female-specific astrocytic response in AD spinal cord pathology. Our data also show an increase in free cholesterol (Filipin+ area) in 5xFAD mice at 9 months relative to WT controls, accompanied by altered expression of cholesterol metabolism genes, including downregulation of , and . Collectively, these findings provide new insights into AD progression in the spinal cord, highlighting molecular pathology of AD extending beyond the brain. - Source: PubMed
Publication date: 2026/04/17
Wang XiaochuanHarnett WilliamShu XinhuaJiang Hui-Rong - CYP46A1 converts cholesterol to 24-hydroxycholesterol, the principal mechanism for brain cholesterol removal and turnover. CYP46A1 can be allosterically activated with low-dose anti-HIV drug efavirenz and mitigate the manifestations of various neurologic diseases in mouse models and Niemann-Pick type C disease in humans. Yet the underlying reasons for such a broad range of efavirenz therapeutic effects are currently unknown. Here 5XFAD mice, a model of Alzheimer's disease, were treated with low-dose efavirenz, and assessed for changes in their brain proteome, acetylproteome, and metabolome. Sex-independent increases in brain levels of phosphatidylcholines, sphingomyelins, and certain amino acids were documented, and various functional enrichments were identified. The most notable related to brain energy production, vascularization, and prevention of glutamatergic overactivation. Unexpectedly, these and many other enrichments were mediated by different proteins in female and male 5XFAD mice. Efavirenz treatment of 5XFAD mice was repeated, and energy-related compounds were quantified in the brain after in vivo isotopic labeling. Cerebral vasculature was assessed as well. We found increased glycolysis branching, carbon flux through the tricarboxylic acid cycle, and use of alternative energy sources (fatty acids, ketone bodies, and amino acids). Sex-independent improvements in brain vascularization and integrity of the blood-brain barrier were also documented. Collectively, our data suggested that CYP46A1 activation by efavirenz increases brain metabolic flexibility and thereby brain energetics. This enables the increase in production of the building blocks for cellular and tissue repair and rescue of brain pathology, thus explaining the therapeutic benefits for the broad spectrum of neurologic disorders. - Source: PubMed
Publication date: 2026/04/30
Mast NataliaBederman IlyaEl-Darzi NicolePikuleva Irina A - Epilepsy, particularly drug-resistant epilepsy, remains a significant clinical challenge, with many patients failing to achieve seizure control through conventional antiseizure medications. This unmet need has directed research toward alternative therapeutic targets, including neurosteroid modulation and novel molecular pathways. Soticlestat, a selective inhibitor of cholesterol 24-hydroxylase, is a mechanistically distinct investigational approach to epilepsy treatment by modulating mechanisms beyond those targeted by traditional antiseizure medication. Early-phase clinical trials and preclinical studies demonstrated soticlestat's potential in reducing seizure frequency and highlighted additional benefits related to quality-of-life improvements in epilepsy patients. However, recent Phase III trials in Dravet syndrome and Lennox-Gastaut syndrome reported mixed results. Beyond seizure control, soticlestat mechanism of action may offer neuroprotective effects, potentially addressing neurodegeneration and neuroinflammation associated with chronic epilepsy, which could support improved cognitive outcomes over time. These findings underscore the need for further research to elucidate the long-term benefits and potential synergy of soticlestat in combination with other antiseizure medications across diverse epilepsy syndromes. While challenges remain, soticlestat offers a promising therapeutic avenue for improving outcomes in DRE and warrants continued investigation as a potential adjunctive treatment. - Source: PubMed
Publication date: 2026/04/08
Dell'Isola Giovanni BattistaCosta CinziaTozzi AlessandroRoberti RobertaRusso EmilioFerrara PietroSalpietro VincenzoVerrotti Alberto - There remains a need for new treatments for Lennox-Gastaut syndrome (LGS), a developmental and epileptic encephalopathy with a heterogenous patient population that often requires polytherapy. The phase 3, randomized SKYWAY study (NCT04938427) investigated the efficacy and safety of the cholesterol 24-hydroxylase inhibitor soticlestat (TAK-935) in participants with LGS. - Source: PubMed
Publication date: 2026/03/27
Guerrini RenzoMarsh Eric DLiao Wei-PingImai KatsumiKravljanac RuzicaAltmann AnnaHahn Cecil DAuvin StéphaneSchiemann JimmyKhan YasirMitra PranabSheikh Sarah Ivon Rosenstiel PhilippAsgharnejad MahnazDlugos DennisMurthy Venkatesha - Rett syndrome (RTT) is a neurodevelopmental disorder characterized by motor deficits, partly attributed to cerebellar dysfunction. RTT is primarily caused by mutations in the gene encoding the methyl-CpG-binding protein 2 (MECP2), which has been implicated in cholesterol homeostasis by mechanisms that remain poorly understood. Given that brain cholesterol is primarily synthesized de novo and that disrupted cholesterol homeostasis is linked to various neurological disorders, we aimed to investigate cholesterol regulation in the cerebellum of -null mice, a well-established RTT model. We measured total cholesterol levels in cerebellar tissue and cerebellar synaptosomes and assessed the expression of genes involved in cholesterol biosynthesis and intracellular transport. Our results show significantly elevated total cholesterol in both cerebellar tissue and synaptosomes. Furthermore, we identified a marked reduction in expression, which is essential for the elimination of encephalon sterols. In contrast, key cholesterol biosynthetic regulators (, , ) showed no significant changes in expression, suggesting an impaired cerebellar cholesterol turnover-driven by defective clearance-rather than enhanced synthesis may underlie the metabolic imbalance observed in the cerebellum of the RTT mouse model. Altogether, these findings provide a mechanistic insight into how MeCP2 deficiency disrupts cerebellar cholesterol homeostasis and highlight cholesterol clearance pathways as potential contributors to RTT pathology and a factor to consider for further RTT therapeutic approaches. - Source: PubMed
Publication date: 2026/03/03
Tapia Pablo JRivera Bastian IEspinoza C SofíaStolzenbach FranciscaYáñez María JKerr Bredford