Characterization and functional studies of lipoproteins, lipid transfer proteins, and lecithin:cholesterol acyltransferase in CSF of normal individuals and patients with Alzheimer's disease

Abstract

We investigated the lipoprotein distribution and composition in cerebrospinal fluid (CSF) in a group of patients with Alzheimer's disease (AD) or affected by other types of dementia in comparison to non-demented controls. We found slightly decreased apolipoprotein (apo)E and cholesterol concentrations in CSF of AD patients and moderately increased apoA-I concentrations, while in patients suffering from other types of dementia the apoA-I CSF concentration was increased. ApoA-IV concentrations varied widely in human CSF, but were not associated with any clinical condition. HDL 2 -like apoE-containing lipoproteins represent the major lipoprotein fraction. In CSF of normal controls, only a minor HDL 3 -like apoA-I-containing lipoprotein fraction was observed; this fraction was more prevalent in AD patients. ApoA-II was recovered mostly in the HDL 3 density range, while apoA-IV was not associated with lipoproteins but appeared in a lipid-free form, co-localizing with LCAT immunoreactivity. Bi-dimensional analysis demonstrated pre-␤ and ␣ apoA-I-containing particles; apoE and apoA-II were detected only in ␣ -migrating particles. ApoA-IV distributed both to pre-␤ and ␥ -migrating particles; the LCAT signal was co-localized in this ␥ -migrating fraction. Enzymatically active LCAT was present in human CSF as well as PLTP activity and mass; no CETP mass was detected. In CSF from AD patients, LCAT activity was 50% lower than in CSF from normal controls. CSF lipoproteins induced a significant cholesterol efflux from cultured rat astrocytes, suggesting that they play an active role in maintaining the cholesterol homeostasis in brain cells. -Demeester, N., G.

Characterization of four lipoprotein classes in human cerebrospinal fluid

“…Fatty acids are not catabolized in the brain, which depends on glucose for energy supply; however, fatty acids as components of phospholipids are of great structural importance in the membranes of neurons. Data on enzymes involved in lipid metabolism, such as phospholipases, esterases, and hydrolases, are given in Davson and Segal (35), as well as in a publication by Demeester et al (36). Lipoprotein lipase is expressed in the brain and hydrolytic activity has been measured in various regions (37,38).…”

Molecular characterization of rabbit phospholipid transfer protein: choroid plexus and ependyma synthesize high levels of phospholipid transfer protein

“…5), strengthening the notion that PLTP is indeed synthesized locally within the central nervous system (CNS). Even in humans, with clearly lower levels of PLTP mRNA in the CNS, recently PLTP activity and mass was shown to be present in cerebrospinal fluid (50), averaging about 1% of plasma values. This seemingly low level of activity should be seen in the context of cerebrospinal fluid lipid and apoA-I (51) concentrations, which also average about 1% of plasma levels, indicating that PLTP activity, even in humans, clearly has the potential to substantially modulate the metabolism of lipoproteins in cerebrospinal fluid.…”

“…Recently, a growing body of evidence supports an important role of cerebrospinal fluid lipoproteins in the transport of essential fatty acids, lipid-soluble vitamins, cholesterol, and also in the removal of oxysterols formed by degenerative processes ( 51). A number of components of the lipid transport system in cerebrospinal fluid, such as some apolipoproteins (i.e., apoE, apoD, and apoJ), receptors (i.e., LDL-receptor, LRP, and megalin), and enzymes [i.e., LCAT (50)] are synthesized locally, others are imported from plasma [i.e., apoA-I (51, 54)]. Our data add PLTP to the roster of enzymes secreted by mammalian brain and detail its neuroanatomical localization.…”

Understanding the Exchange of Systemic HDL Particles Into the Brain and Vascular Cells Has Diagnostic and Therapeutic Implications for Neurodegenerative Diseases

“…While the structural, chemical, and functional properties of plasma HDL-P have been extensively studied, the properties of CSF HDL-P remain elusive due to their low abundance and high complexity ( Montine et al, 1998 ; Yamauchi et al, 1999 ; Demeester et al, 2000 ; Koch et al, 2001 ; Yassine et al, 2016 ). Methods using gradient gel electrophoresis ( Remaley et al, 2001 ), ion-mobility analysis (IMA), and nuclear magnetic resonance (NMR) spectroscopy have characterized three major groups of HDL-P in plasma by particle size: small (7–8.5 nm), medium (8.5–10.5 nm), and large (10.5–15 nm) ( Nichols et al, 1986 ; Otvos et al, 1992 ; Jeyarajah et al, 2006 ; Caulfield et al, 2008 ).…”

“…As shown in Figure 1 and Table 1 , some plasma-derived proteins are known to traverse the BCSFB. For example, while apoA-I and apoA-II mRNAs are not expressed in brain cells, they are present in the CSF and have been associated with CNS lipoproteins ( Demeester et al, 2000 ). Stukas et al (2014a) identified that the majority of intravenously injected lipid-free apoA-I was found in the CP in vivo .…”