Cholesterol Metabolism in CNS Diseases: The Potential of SREBP2 and LXR as Therapeutic Targets

The brain is the organ with the highest cholesterol content in the body. Cholesterol in the brain plays a crucial role in maintaining the integrity of synapses and myelin sheaths to ensure normal brain function. Disruptions in cholesterol metabolism are closely associated with various central nervous system (CNS) diseases, including Alzheimer's disease (AD), Huntington's disease (HD), and multiple sclerosis (MS). In this review, we explore the synthesis, regulation, transport, and functional roles of cholesterol in the CNS. We discuss in detail the associations between cholesterol homeostasis imbalance and CNS diseases including AD, HD, and MS, highlighting the significant role of cholesterol metabolism abnormalities in the development of these diseases. Sterol regulatory element binding protein-2 (SREBP2) and liver X receptor (LXR) are two critical transcription factors that play central roles in cholesterol synthesis and reverse transport, respectively. Their cooperative interaction finely tunes the balance of brain cholesterol metabolism, presenting potential therapeutic value for preventing and treating CNS diseases. We particularly emphasize the alterations in SREBP2 and LXR under pathological conditions and their impacts on disease progression. This review summarizes current therapeutic agents targeting these two pathways, with the hope of broadening the perspectives of CNS drug developers and encouraging further study into SREBP2 and LXR-related therapies for CNS diseases.