Cholesterol serves as an essential lipid molecule in various membrane organelles of mammalian cells. The metabolites of cholesterol also play important functions. Acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1), also named as sterol O-acyltransferase 1, is a membrane-bound enzyme residing at the endoplasmic reticulum (ER). It converts cholesterol to cholesteryl esters (CEs) for storage, and is expressed in all cells. CEs cannot partition in membranes; they can only coalesce as cytosolic lipid droplets. Excess CEs are found in the vulnerable region of the brains of patients with late-onset Alzheimer’s disease (AD), and in cell and mouse models for AD. Reducing CE contents by genetic inactivation of ACAT1, or by pharmacological inhibition of ACAT is shown to reduce amyloidopathy and other hallmarks for AD. To account for the various beneficial actions of the ACAT1 blockade (A1B), a working hypothesis is proposed here: the increase in CE contents observed in the AD brain is caused by damages of cholesterol-rich lipid rafts that are known to occur in neurons affected by AD. These damages cause cholesterol to release from lipid rafts and move to the ER where it will be converted to CEs by ACAT1. In addition, the increase in CE contents may also be caused by overloading with cholesterol-rich substances, or through activation of ACAT1 gene expression by various pro-inflammatory agents. Both scenarios may occur in microglia of the chronically inflamed brain. A1B ameliorates AD by diverting the cholesterol pool destined for CE biosynthesis such that it can be utilized more efficiently to repair membrane damage in various organelles, and to exert regulatory actions more effectively to defend against AD. To test the validity of the A1B hypothesis in cell culture and in vivo, the current status of various anti-ACAT1 agents that could be further developed is briefly discussed.

The brain cholesterol content is determined by the balance between the pathways of in situ biosynthesis and cholesterol elimination via 24-hydroxylation catalyzed by cytochrome P450 46A1 (CYP46A1). Both pathways are tightly coupled and determine the rate of brain cholesterol turnover. Evidence is accumulating that modulation of CYP46A1 activity by gene therapy or pharmacologic means could be beneficial in the case of neurodegenerative and other brain diseases and affect brain processes other than cholesterol biosynthesis and elimination. This minireview summarizes these other processes, most common of which include abnormal protein accumulation, memory, and cognition, motor behavior, gene transcription, protein phosphorylation as well as autophagy and lysosomal processing. The unifying mechanisms, by which these processes could be affected by CYP46A targeting are also discussed.

Niemann-Pick C disease is a rare neurodegenerative, lysosomal storage disease caused by accumulation of unesterified cholesterol. Diagnosis of the disease is often delayed due to its rarity, the heterogeneous presentation, and the early non-specific symptoms. The discovery of disease-specific biomarkers—cholestane-3β,5α,6β-triol (C-triol), trihydroxycholanic acid glycinate (TCG) and N-palmitoyl-O-phosphocholineserine [PPCS, initially referred to as lysosphingomyelin-509 (lysoSM-509)]—has led to development of non-invasive, blood-based diagnostics. Dissemination of these rapid, sensitive, and specific clinical assays has accelerated diagnosis. Moreover, the superior receiver operating characteristic of the TCG bile acid biomarker and its detection in dried blood spots has also facilitated development of a newborn screen for NPC, which is currently being piloted in New York state. The C-triol, TCG and PPCS biomarkers have also been proved useful for monitoring treatment response in peripheral tissues, but are uninformative with respect to treatment efficacy in the central nervous system (CNS). A major gap for the field is the lack of a validated, non-invasive biomarker to monitor the course of disease and CNS response to therapy.

Peroxisomes are actively involved in the metabolism of various lipids including fatty acids, ether phospholipids, bile acids as well as the processing of reactive oxygen and nitrogen species. Recent studies show that peroxisomes can regulate cholesterol homeostasis by mediating cholesterol transport from the lysosomes to the endoplasmic reticulum and towards primary cilium as well. Disruptions of peroxisome biogenesis or functions lead to peroxisomal disorders that usually involve neurological deficits. Peroxisomal dysfunction is also linked to several neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. In many peroxisomal disorders and neurodegenerative diseases, aberrant cholesterol accumulation is frequently encountered yet largely neglected. This review discusses the current understanding of the mechanisms by which peroxisomes facilitate cholesterol trafficking within the cell and the pathological conditions related to impaired cholesterol transport by peroxisomes, with the hope to inspire future development of the treatments for peroxisomal disorders and neurodegenerative diseases.