HDL and cognition in neurodegenerative disorders

Highlights

• Multifunctional HDL particles are formed both in the periphery and in the brain.

• HDL metabolism pathways modulate the progress of neurodegenerative disorders.

• Elevated levels of HDL preserve cognition in aging and neurodegenerative disorders.

• HDL-enhancing therapies may be applied to improve cognitive function.

Abstract

High-density lipoproteins (HDLs) are a heterogeneous group of lipoproteins composed of various lipids and proteins. HDL is formed both in the systemic circulation and in the brain. In addition to being a crucial player in the reverse cholesterol transport pathway, HDL possesses a wide range of other functions including anti-oxidation, anti-inflammation, pro-endothelial function, anti-thrombosis, and modulation of immune function. It has been firmly established that high plasma levels of HDL protect against cardiovascular disease. Accumulating evidence indicates that the beneficial role of HDL extends to many other systems including the central nervous system. Cognition is a complex brain function that includes all aspects of perception, thought, and memory. Cognitive function often declines during aging and this decline manifests as cognitive impairment/dementia in age-related and progressive neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. A growing concern is that no effective therapy is currently available to prevent or treat these devastating diseases. Emerging evidence suggests that HDL may play a pivotal role in preserving cognitive function under normal and pathological conditions. This review attempts to summarize recent genetic, clinical and experimental evidence for the impact of HDL on cognition in aging and in neurodegenerative disorders as well as the potential of HDL-enhancing approaches to improve cognitive function.

Introduction

Lipoproteins are the complexes of various lipids and proteins (Vance and Vance, 2008). They are formed in extracellular space and circulate as soluble subcellular-sized particles in body fluids. The general structure of lipoprotein particles includes a hydrophobic core surrounded by a hydrophilic shell. The hydrophobic core contains neutral lipids, predominantly triglycerides (TGs) and cholesterol esters (CEs). The hydrophilic shell consists of primarily phospholipids (PL), unesterified free cholesterol (FC), and various apolipoproteins (apos), which mediate interactions with a variety of other molecules including enzymes, transporters, and receptors through a dynamic process. The main function of lipoproteins is facilitating the delivery and clearance of lipids and lipid-soluble or lipid-associating molecules throughout the body. Lipoproteins can be characterized by their size, density, electrophoretic mobility, and composition. The most commonly used classification of lipoproteins is by density. Due to the dynamic nature of lipoproteins, each class of lipoproteins can be divided into several subclasses. The focus of this review is on high-density lipoprotein (HDL), a heterogeneous group of lipoprotein particles with a density of 1.063–1.210 g/mL and size of approximately 7–20 nm. They are formed both in the systemic circulation and in the brain. Plasma HDL has been studied extensively because of its well established protective role in the cardiovascular system. Recent studies strongly suggest that the benefits of HDL extend to many other systems including the central nervous system (CNS). Mounting evidence indicates that HDL modulates cognitive function in aging and age-related neurodegenerative disorders.

Major neurodegenerative disorders include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). In these diseases, specific areas of the CNS deteriorate progressively, resulting in devastating neurological dysfunction. AD is a cognitive disorder that causes the most common form of dementia, accounting for 50–60% of all cases (Alzheimer's Association, 2013). Although PD, HD, and ALS are considered primarily as movement disorders, cognitive impairment/dementia is found in substantial groups of patients with these diseases (Goldstein and Abrahams, 2013, Svenningsson et al., 2012, Walker, 2007). Much progress has been made on the etiology and pathogenic mechanisms of these neurodegenerative disorders; however, currently there are still no effective measures to prevent or treat these debilitating diseases. Emerging evidence suggests that HDL modulates cognitive function under normal and pathological conditions. This review provides an overview of HDL function in the systemic circulation and in the brain, summarizes recent genetic, clinical and experimental evidence for the impact of HDL on cognition in aging and in neurodegenerative disorders, and explores the potential of HDL-enhancing approaches to improve cognitive function.