Apolipoprotein E does not cross the blood-cerebrospinal fluid barrier, as revealed by an improved technique for sampling CSF from mice

Abstract

-Apolipoprotein E (apoE) is a 34-kDa glycoprotein that is important in lipoprotein metabolism both peripherally and centrally. Because it is primarily produced in the liver, apoE observed in the brain or cerebrospinal fluid (CSF) could have originated in the periphery; i.e., circulating apoE may cross the blood-brain barrier (BBB) and/or enter CSF and be taken up by brain cells. To determine whether this occurs, a secondgeneration adenovirus encoding human apoE3 was administered intravenously (iv) to C57BL/6J mice, and the detection of human apoE3 in the CSF was used as a surrogate measure of central availability of this protein utilizing an improved method for sampling CSF from mice. This improved technique collects mouse CSF samples with a 92% success rate and consistently yields relatively large volumes of CSF with a very low rate of blood contamination, as determined by molecular assessment of apolipoprotein B, a plasma-derived protein that is absent in the central nervous system. Through this improved method, we demonstrated that in mice receiving the administered apoE3 adenovirus, human apoE3 was expressed at high levels in the liver, leading to high levels of human apoE3 in mouse plasma. In contrast, human apoE3 levels in the CSF, as assessed by a sensitive ELISA, were essentially undetectable in human apoE3 adenovirustreated mice, and comparable to levels in LacZ adenovirus-treated control mice. These data indicate that apoE in the CSF cannot be derived from the plasma pool and, therefore, must be synthesized locally in the brain.cerebrospinal fluid collection; cisternum magnum; adenovirus; apolipoprotein E APOLIPOPROTEIN E (APOE) IS a 299-amino acid protein with a 34-kDa molecular weight (33). Although it is synthesized in several areas of the body, the liver accounts for most circulating apoE (19). ApoE plays a key role in lipid transport and lipoprotein metabolism (18). It mediates the uptake and degradation of chylomicron and very low-density lipoprotein remnants by acting as a ligand for the low-density lipoprotein (LDL) receptor and the LDL receptor-related protein 1 (LRP1) (1, 18). Because apoE is involved directly in the uptake and distribution of plasma lipids, it is not surprising that it has been implicated in cardiovascular disease, and apoE deficiency is associated with high serum cholesterol and triacylglycerol levels and leads to premature artherosclerosis (23).ApoE is also present in the brain. Central apoE is the most abundant component of HDL-like lipoproteins in the cerebrospinal fluid (CSF) (22), and it has a pivotal role in brain lipid transport and the maintenance of cell membranes, myelin, and neural networks under normal conditions (3, 11). Recently, we demonstrated that central apoE is important in the control of food intake and body weight (27,28), and these effects might be mediated by the LRP1 receptor (16). Because apoE is present in both blood and CSF, any apoE found in the brain could have originated in the periphery; i.e., circulating apoE may cross the blood-brain barrier...

Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation

“…The CNS relies primarily on de novo synthesis of apoE, since the blood–brain barrier (BBB) restricts the transport of apoE and cholesterol into and out of brain [6–8]. Mature neurons have a high demand for cholesterol and while they can synthesize it, under physiological conditions additional supplement in the form of apoE-associated cholesterol is used [9].…”

Low Plasma ApoE Levels Are Associated with Smaller Hippocampal Size in the Alzheimer's Disease Neuroimaging Initiative Cohort

“…This mechanism might be expected to be more relevant to ApoE levels in the brain than in the plasma, but previous work with transgenic APOE mice indicates that APOE genotype has similar effects on brain and plasma ApoE levels [15]. Although ApoE does not appear to cross the blood-brain barrier [40], ApoE levels and isoforms modulate Aβ clearance from the plasma [41], which may in turn affect Aβ clearance from the brain.…”

What are lipoproteins doing in the brain?

“…However, when mice are injected with adenovirus containing human apoE isoform 3 (apoE3), ApoE3 protein is found in plasma lipoproteins at high levels, yet remains undetectable in CSF 7 . In brain, ApoE is expressed predominantly by astrocytes and microglia, and in reduced quantity in neurons, while ApoJ is expressed in astrocytes, neurons, and the ependymal cells lining the ventricle 8 .…”