Brain Phospholipid Metabolism and Aging

Aging

Investigators

Linked publications & trials

Abstract

(1): A rapid method was developed to quantify brain concentrations of coenzyme A (CoA) and short-chain acyl-CoA's. The method employs CoA isolation using an oligonucleotide purification cartridge and high-performance liquid chromatography. In adult rats subjected to 5 min of complete ischemia, the brain concentration of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) was 12-fold compared to the control concentration. This elevation reflected interruption of cholesterol and isoprenoid synthesis by ischemia. (2): Positron emission tomography (PET) was used with intravenously injected [1-11C]arachidonic acid to measure regional rates of incorporation of arachidonic acid into different brain regions in 8 young human adults. These rates of incorporation reflect regional post-synaptic phospholipase A2 activation. They now can be measured in the human brain at rest and during activation in relation to aging and disease. (3): Brain lipid metabolism had been thought to consume only 2% of the ATP produced by oxidative metabolism. However, a stoichiometric analysis of the rates of different lipid metabolic pathways that consume ATP showed that lipid metabolism consumes at least 20% of the brain's net ATP production. This high value is consistent with active roles of lipids in brain signal transduction and membrane remodeling. (4,6): Defective brain serotonin (5-HT) neurotransmission contributes to depression and Alzheimer disease, but has never been imaged in living animals or humans. We developed a method to do this. Administration to awake rats of the postsynaptic 5-HT2 receptor agonist, (+-)-2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI), stimulated brain incorporation of intravenously injected labeled arachidonic acid, a marker of phospholipase A2 activation coupled to the 5-HT2 receptors. The stimulation could be blocked by a 5-HT2 antagonist. (5,6): Fluoxetine, a selective serotonin reuptake inhibitor, is used to treat human depression. By inhibiting presynaptic 5-HT reuptake, it increases 5-HT in the synaptic cleft, thus 5-HT binding to postsynaptic 5-HT2 receptors coupled to phospholipase A2. We imaged activation of phospholipase A2 by fluoxetine in awake rats using radiolabeled arachidonic acid and quantitative autoradiography. Tracer uptake was increased in regions with high densities of the serotonin reuptake transporter. This activation may be related to fluoxetine's therapeutic clinical effect. (7): The cytosolic phospholipase A2 (cPLA2) is located at post-synaptic sites in brain neurons, and participates in receptor-initiated signaling involving arachidonic acid. Mice with this enzyme knocked out demonstrated altered brain concentrations of phospholipids and of esterified arachidonic and docosahexaenoic acids, and altered arachidonate turnover rates. Thus, cPLA2 is necessary for maintaining normal brain phospholipid metabolism and normal postsynaptic signaling involving arachidonic acid.