HDL: Close to Our Memories?

Abstract

T he last decade has witnessed an explosion in studies of the role of lipoproteins in brain function. Neurons require a continuous supply of lipids for membrane synthesis and acetylcholine production. Indeed, the brain is a site of intense lipid turnover-even though the central nervous system (CNS) accounts for only 2.1% of body weight, it contains 23% of total body cholesterol. 1 Lipid metabolism in the brain is tightly controlled locally, as plasma lipoproteins are shielded from the brain by the blood-brain barrier. Although neuronal cells are capable of de novo synthesis of a wide spectrum of molecular species of lipids, they rely heavily on exogenous sources and readily bind and internalize lipoproteins of the extracellular fluid. 2 Equally, neurons need to dispose of excess lipids; lipoprotein-mediated lipid transport is therefore bidirectional and includes cellular efflux of cholesterol. 3 See accompanying article on page 1556Human cerebrospinal fluid (CSF) primarily contains spherical lipoproteins of approximately 10 to 12 nm in diameter with hydrated density in the range 1.063 to 1.25 g/mL, thereby resembling HDL in human plasma. 3,4 Lipid concentrations in CSF are however much lower (eg, 300-to 400-fold for total cholesterol and phospholipids) as compared to the plasma compartment. 4 Apolipoproteins (apo) E and A-I are the major apolipoproteins in human CSF (typical concentration range: 0.1 to 0.4 mg/dL 3,4 ), with apoA-II, A-IV, J, D, C-II, C-III, C-IV, and H equally present. 3,4 Importantly, CSF lipoproteins carry amyloid-␤ (A␤), a 39-to 43-aa peptide produced in neuronal cells, which is the major component of senile amyloid plaques. 5 The metabolism of CSF lipoproteins remains poorly characterized but seems to be distinct from that of plasma lipoproteins. ApoE-rich HDL are synthesized locally in CNS and secreted by astrocytes as discoidal complexes enriched in free cholesterol. 6 High apoE content targets these lipoproteins to cellular apoE receptors, particularly LDL receptor-related protein, which is abundantly expressed on the surface of neurons. 2 By contrast, apoA-I-rich CSF lipoproteins are most probably derived from plasma HDL that enter the CNS by crossing the blood-brain barrier, 7 as apoA-I is not synthesized in the CNS. 2 Similar to plasma HDL, CSF lipoproteins can be remodeled by lecithin-cholesterol acyltransferase and phospholipid transfer protein; by contrast, cholesteryl ester transfer protein (CETP) is absent from CSF. 3 These data clearly demonstrate that brain HDL constitute a key element of cholesterol homeostasis in the CNS.Over the past decade, abnormalities in brain lipid metabolism are increasingly recognized to be intimately related to the pathogenesis of such major neurodegenerative disorders as Alzheimer disease (AD) and vascular dementia (VD). With respective frequencies of 70% and 15% of all dementias, AD and VD are the most common forms of dementia which are typically preceded by less dramatic cognitive decline, including decline in memory. 8 Both AD and atherosclerosis ...

Overexpression of Human Apolipoprotein A-I Preserves Cognitive Function and Attenuates Neuroinflammation and Cerebral Amyloid Angiopathy in a Mouse Model of Alzheimer Disease

“…Several potential mechanisms have been proposed (58,59). One of the major protective functions of apoA-I/HDL relates to its antioxidative and anti-inflammatory properties.…”

HDL-cholesterol and apolipoproteins in relation to dementia

“…Apolipoproteins combine with cholesterol to form soluble lipoproteins that serve as transporters in aqueous solutions, including both blood and cerebrospinal fluid (CSF) circulating within the ventricles of the brain. Several apolipoproteins including apoE, apoA-I, and apoJ [6, 7, 8] are found in CSF where they combine with cholesterol to form lipoproteins that are relatively higher in protein (concentrations), and thus have densities similar to plasma high-density lipoprotein cholesterol (HDL-C) [9]. Apolipoproteins are involved in the deposition and clearance of beta-amyloid, a determining factor for subsequent neurodegeneration [10, 11, 12].…”

“…As opposed to studies using CSF, the investigation of blood markers is intriguing for the potential to identify novel non-invasive biomarkers for dementia. Plasma levels of HDL are typically indicated by either the cholesterol concentration in HDL or by measurement of plasma apoA-I concentrations, the key protein component in HDL in plasma [9]. Interestingly, even apolipoproteins such as apoA-I and apoC-III that are not expressed in the brain, are also found in CSF, indicating they are able to cross the blood brain barrier [7, 8, 15].…”

Phospholipid Transfer Protein Is Expressed in Cerebrovascular Endothelial Cells and Involved in High Density Lipoprotein Biogenesis and Remodeling at the Blood-Brain Barrier

“…Our findings, collectively, underline a crucial role for PLTP in HDL metabolism at the BBB. It has been documented that HDL particles mediate clearance of A␤ from cells (52,53). Because we here revealed a critical role for PLTP in HDL biogenesis at the BBB, we assumed that it might be also involved in the regulation of A␤ homeostasis.…”