24S-Hydroxycholesterol in Neuropsychiatric Diseases: Schizophrenia, Autism Spectrum Disorder, and Bipolar Disorder.

Abstract

Neuropsychiatric diseases (NPDs) are severe, debilitating psychiatric conditions that affect the nervous system. These are among the most challenging disorders in medicine. Some examples include Alzheimer's, anxiety disorders, autism spectrum disorder, bipolar disorder, and schizophrenia. NPDs represent an ever-increasing burden on public health and are prevalent throughout the world. For most of these diseases, the particular etiopathogeneses are still enigmatic. NPDs are also associated with structural and functional changes in the brain, along with altered neurotransmitter and neuroendocrine systems.Approximately 25% of the total human body cholesterol is located in the brain. Its involvement in neuronal functions starts in the early growth stages and remains important throughout adulthood. It is also an integral part of the neuronal membrane, ensuring membrane lipid organization and regulating membrane fluidity. The main mechanism for removing cholesterol from the brain is cholesterol 24-hydroxylation by cytochrome P450 46A1 (CYP46A1), an enzyme specifically found in the central nervous system. Although research on 24S-OHC and its role in neuropsychiatric diseases is still in its early stages, this oxidized cholesterol metabolite is thought to play a crucial role in the etiology of NPDs. 24S-OHC can affect neurons, astrocytes, oligodendrocytes, and vascular cells. In addition to regulating the homeostasis of cholesterol in the brain, this oxysterol is involved in neurotransmission, oxidative stress, and inflammation. The role of 24S-OHC in NPDs has been found to be controversial in terms of the findings so far. There are several intriguing discrepancies in the data gathered so far regarding 24S-OHC and NPDs. In fact, 24S-OHC levels were reported to have decreased in a number of NPDs and increased in others.Hence, in this chapter, we first summarize the available data regarding 24S-OHC as a biomarker in NPDs, including schizophrenia, autism spectrum disorder, and bipolar disorder. Then, we present a brief synopsis of the pharmacological targeting of 24S-OHC levels through the modulation of CYP46A1 activity.