HDL and cognition in neurodegenerative disorders

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.

Fig. 1. Schematic of HDL metabolism in the systemic circulation

Formation of the nascent discoidal HDL through apoA-I and ABCA1 is the first step in reverse cholesterol transport (RCT), a process that removes excess cholesterol from peripheral tissues to the liver for excretion. In the plasma, apoA-I activates LCAT, which converts discoidal HDL to mature, spherical, CE-rich HDL particles. HDL interacts with other lipoprotein particles and cells through multiple receptors, transporters, and enzymes. Mature HDL removes cholesterol from peripheral cells through other ABC transporters such as ABCG1. Lipid-rich HDL selectively delivers CE to hepatocytes and steroidogenic cells through SR-B1. HDL-bound CETP mediates the exchange of CE and TG between HDL and non-HDL particles. ABC, ATP-binding cassette transporter; Apo, apolipoprotein; CE, cholesteryl esters; CETP, cholesteryl ester transfer protein; FC, unesterified free cholesterol; HDL, high-density lipoproteins; LCAT, lecithin cholesterol acyltransferase; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; PL, phospholipids; SR-B1, scavenger receptor B1; TG, triglycerides.

Fig. 2. Schematic of HDL metabolism in the brain

Similar to peripheral tissues, the brain expresses various lipoprotein receptors (e.g., LDLR, LRP, and SR-B1), enzymes (e.g., LCAT and lipases), transfer proteins (e.g., PLTP and CETP), and ABC transporters (e.g., ABCA1 and ABCG1). However, the presence of CETP in the brain is controversial. ApoE, synthesized primarily by glia, and apoA-I from the blood generate HDL particles and mediate cholesterol efflux through interactions with ABCA1 and ABCG1. LCAT converts the discoidal HDL to mature HDL particles. The HDL particles are remodeled by the interactions of apoE and apoA-I with various lipoprotein receptors on neurons and glia. ABC, ATP-binding cassette transporter; ACAT, acyl-coenzyme A:cholesterol acyltransferase; Apo, apolipoprotein; BBB, blood-brain barrier; CE, cholesteryl esters; CETP, cholesteryl ester transfer protein; FC, unesterified free cholesterol; HDL, high-density lipoproteins; LCAT, lecithin cholesterol acyltransferase; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; LRP, low-density lipoprotein receptor-related protein; PL, phospholipids; SR-B1, scavenger receptor B1; TG, triglycerides.

Fig. 3. Schematic of potential mechanisms by which apoA-I/HDL modulates the disease process related to AD

ApoA-I is hypothesized to act on five major pathways to exert its neuroprotective effects pertinent to AD. (1) Cholesterol efflux pathway: ApoA-I in the brain promotes the cellular cholesterol efflux through ABCA1 and forms HDL-like particles. These particles are cleared by interacting with receptors such as SR-B1 by cells in the brain or through the BBB to peripheral circulation. (2) APP trafficking and processing pathway: ApoA-I-mediated increase in membrane fluidity may enhance α-secretase cleavage of APP at the cell membrane. Also, apoA-I binds to the extracellular domain of APP, which may prevent APP from undergoing the endocytic process, thereby inhibiting the access of β- and γ-secretases to APP and reducing the generation of Aβ. (3) Aβ clearance pathway: ApoA-I binds to Aβ and inhibits Aβ aggregation. ApoA-I/HDL in the brain can mediate the clearance of Aβ by local cells (e.g., astrocytes and microglia) through the scavenger receptor (e.g., SR-B1) and/or by crossing the BBB to the systemic circulation. (4) Anti-oxidation and anti-inflammation: ApoA-I/HDL possesses anti-oxidant and anti-inflammatory properties that are neuroprotective. (5) Signal transduction and synaptic plasticity: ApoA-I/HDL activates several kinases and increases the level of cAMP directly or indirectly through ABCA1 or SR-B1. These molecules play important roles in signaling pathways pertinent to synaptic function and memory formation. ABC, ATP-binding cassette transporter; ApoA-I, apolipoprotein A-I; Aβ, amyloid-β protein; APP, amyloid-β precursor protein; BBB, blood-brain barrier; cAMP, cyclic AMP; CE, cholesterol esters; eNOS, endothelial nitric oxide synthase; FC, unesterified free cholesterol; HDL, high-density lipoproteins; LCAT, lecithin cholesterol acyltransferase; PL, phospholipids; NO, nitric oxide; sAPPα, soluble N-terminal fragment of APP produced by α-secretase cleavage; 24S-HO-Chol, 24S-hydroxycholesterol; SR-B1, scavenger receptor B1.