A new role for apolipoprotein E: modulating transport of polyunsaturated phospholipid molecular species in synaptic plasma membranes

Abstract

Phospholipids and their acyl group composition are important in providing the proper membrane environment for membrane protein structure and function. In particular, the highly unsaturated phospholipids in synaptic plasma membranes in the CNS are known to play an important role in modulating receptor function and neurotransmitter release processes. Apolipoprotein E (apoE) is a major apolipoprotein in the CNS, mediating the transport of cholesterol, phospholipids and their fatty acids, particularly in reparative mechanisms during neuronal injury. This study was performed to determine whether deficiency in the apoE gene contributes to an alteration of the phospholipids in synaptic plasma membranes. Phospholipid molecular species were identified and quantitated by HPLC/electrospray ionization-mass spectrometry. Analysis of the different phospholipid classes in membranes of apoE-deficient and C57BL/6 J mice indicated no obvious differences in the distribution of different phospholipid classes but substantial differences in composition of phospholipid molecular species. Of special interest was the prevalence of phospholipids (phosphatidylcholine, diacyl-phosphatidylethanolamine, and phosphatidylserine) with 22:6n-3 in both the sn-1 and sn-2 positions of SPM and these phospholipid species were significantly higher in apoE-deficient mice as compared to control mice. Since polyunsaturated fatty acids in neurons are mainly supplied by astrocytes, these results revealed a new role for apoE in regulating polyunsaturated phospholipid molecular species in neuronal membranes.

Amyloid-β42signals tau hyperphosphorylation and compromises neuronal viability by disrupting alkylacylglycerophosphocholine metabolism

“…It may be that the accumulation of hexadecyl-PAFs indicates a shift in substrate availability in diseased tissue consistent with a larger metabolic disruption in lipid metabolism. The loss of apolipoprotein E, for example, a risk factor associated with AD, alters the traffic of polyunsaturated lipids from astrocytes to neurons, biasing the composition of long-chain fatty acids in synaptosomes phosphocholines toward hexadecyl (16:0) species in null-mutant mice (32). Furthermore, the calciumindependent PLA 2 ␥ (iPLA 2 ␥) isoform, capable of hydrolyzing both sn-1 and sn-2 unsaturated fatty acid chains, shows specificity for palmitic acid-containing carbon chains.…”

Lipid homeostasis and apolipoprotein E in the development and progression of Alzheimer's disease

“…The phospholipid composition of neuronal membranes, such as the ratio of membrane -3 to -6 long-chain PUFAs, can be modulated by dietary intake (12), apoE expression (13), and the presence of AD pathology (14,15) (Fig. 1).…”

“…Given the importance of fatty acid/eicosanoid signal transduction in all excitable tissues, it would not be surprising if disturbances in this system were to lead to neurological problems. The balance of dietary -6/ -3 longchain PUFAs may influence levels of neurotransmitters, such as glutamate, acetylcholine (ACh), and dopamine (26)(27)(28)(29)(30), levels of nerve growth factor (31), synaptic membrane function (32,33), the function of membrane proteins (13,18), oxidative stress, lipid peroxidation, antioxidative defense (15,17,(34)(35)(36), glutamate-induced excitotoxicity (37), cerebral blood flow (38,39), ischemic damage (40), blood pressure (41), and cognitive functions (27,33,(42)(43)(44)(45).…”

“…ApoE is involved in the regulation of cholesterol in the outer (exofacial) and inner (cytofacial) leaflets, and in the PUFA content of phospholipid molecular species of the synaptic membrane (13). Changes in synaptic membrane lipid composition result in altered function of membranebound enzymes.…”

“…Both AChE and APOE have roles in A␤ fibrilization (188,219), and BuChE and APOE have roles in lipid metabolism and transport (13,(220)(221)(222). The BuChE-K polymorphism may also influence the risk of AD conferred by the APOE 4 allele (223,224) and may be associated with slower disease progression in patients with moderate AD (225,226).…”