Mechanisms, Mediators, and Pharmacological Approaches Targeting Brain Cholesterol Transport in Alzheimer's Disease

Abstract: Cholesterol transport within the brain represents a highly regulated process essential for maintaining neuronal function and central nervous system (CNS) homeostasis. Unlike peripheral tissues, the brain relies on in situ cholesterol synthesis, primarily by astrocytes and other glial cells, which supply neurons via high-density lipoprotein (HDL)-like particles, identified in the human cerebrospinal fluid (CSF). The major component of HDL-like lipoproteins is the apolipoprotein E (ApoE), whose E4 isoform represents the strongest genetic risk factor for late-onset Alzheimer's disease (AD). Growing evidence suggests that impaired cholesterol transport contributes to the pathogenesis of various neurodegenerative disorders, particularly AD, a major public health concern due to increasing prevalence and the lack of effective treatments. Indeed, the unconvincing outcomes of the amyloid-targeting monoclonal antibodies underscore the urgency of identifying alternative therapeutic strategies. This review provides a comprehensive analysis of cholesterol transport mechanisms within the brain and their dysregulation in AD by examining the astrocyte-to-neuron cholesterol supply pathways, including endogenous biosynthesis, cholesterol efflux from astrocytes, neuronal uptake, and intracellular processing. Key molecular players involved in each step are discussed, focusing on their roles in AD pathophysiology and potential as therapeutic targets. Furthermore, the review critically evaluates recent preclinical studies exploring pharmacological interventions able to modulate cerebral cholesterol homeostasis. These emerging approaches offer promising alternatives to amyloid-based treatments and may open new perspectives for preventing or mitigating neurodegeneration in AD. By providing an integrated overview of cholesterol transport in the brain, this review highlights novel directions for research and drug development targeting CNS cholesterol metabolism.