Emerging role of HDL in brain cholesterol metabolism and neurodegenerative disorders

High-density lipoproteins (HDL) play a key role in cholesterol homeostasis maintenance in the central nervous system (CNS), by carrying newly synthesized cholesterol from astrocytes to neurons, to support their lipid-related physiological functions. As occurs for plasma HDL, brain lipoproteins are assembled through the activity of membrane cholesterol transporters, undergo remodeling mediated by specific enzymes and transport proteins, and finally deliver cholesterol to neurons by a receptor-mediated internalization process. A growing number of evidences indicates a strong association between alterations of CNS cholesterol homeostasis and neurodegenerative disorders, in particular Alzheimer's disease (AD), and a possible role in this relationship may be played by defects in brain HDL metabolism. In the present review, we summarize and critically examine the current state of knowledge on major modifications of HDL and HDL-mediated brain cholesterol transport in AD, by taking into consideration the individual steps of this process. We also describe potential and encouraging HDL-based therapies that could represent new therapeutic strategies for AD treatment. Finally, we revise the main plasma and brain HDL modifications in other neurodegenerative disorders including Parkinson's disease (PD), Huntington's disease (HD), and frontotemporal dementia (FTD).