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Lipids in Human Brain Disease
NATIONAL INSTITUTE ON AGING
Total Funding: $ 857,374
ALZHEIMER DISEASE DISTURBED CHOLINE PLASMALOGEN AND FATTY ACID CONCENTRATIONS IN ALZHEIMER DISEASE BRAIN. Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by senile (neuritic) plaques containing amyloid and neurofibrillary tangles, neuroinflammation, synaptic loss and overexpression of arachidonic acid (AA, 20:4n-6) metabolizing enzymes. Lipid concentration changes have been reported, but partially or as percent of total. We measured absolute lipid concentrations (per gram wet weight) in postmortem prefrontal cortex from 10 AD patients and 9 controls. Total brain lipid, phospholipid, cholesterol, and triglyceride concentrations did not differ significantly between groups. There was a significant 73% decrease in plasmalogen choline, but no difference in other phospholipids. Fatty acid concentrations in total phospholipid did not differ from control. Docosahexaenoic acid (DHA, 22:6n-3) was reduced in ethanolamine glycerophospholipid and choline glycerophospholipid, but increased in phosphatidylinositol. AA was reduced in choline glycerophospholipid, but increased in phosphatidylinositol, while docosatetraenoic acid (22:4n-6), an AA elongation product, was reduced in total lipid, cholesteryl ester and triglyceride. These changes, suggesting extensive membrane remodeling, may contribute to membrane instability and synaptic loss in AD and reflect neuroinflammation and other pathological processes (Igarashi et al., 2011). ALTERED NEUROINFLAMMATORY, ARACHIDONIC ACID CASCADE AND SYNAPTIC MARKERS IN POSTMORTEM ALZHEIMER DISEASE BRAIN. Alzheimers disease (AD) is the leading cause of dementia in the elderly. Our recent positron emission tomography imaging study demonstrated upregulated brain arachidonic acid (AA) metabolism in AD patients, suggestive of inflammation. To test this suggestion, we measured protein and mRNA levels of AA cascade, neuroinflammatory and synaptic markers in postmortem frontal cortex from 10 AD patients and 10 age-matched controls. Consistent with our hypothesis, AD frontal cortex showed significant increases in protein and mRNA levels of cPLA2-IVA, secretory sPLA2-IIA, cyclooxygenase-1 and -2, membrane prostaglandin synthase-1 and lipoxygenase- 12 and -15. Calcium-independent iPLA2-VIA and cytosolic PGE2 synthase were decreased. In addition, interleukin-1b, tumor necrosis factor-a, glial fibrillary acidic protein and CD11b were increased, and synaptophysin and drebrin, pre- and postsynaptic markers, were decreased. These results indicate that increased AA cascade and inflammatory markers could contribute to AD pathology. Altered brain AA cascade enzymes could be therapeutic targets for drug development (Rao et al., In press). DISTURBED NEUROTRANSMITTER TRANSPORTER EXPRESSION IN ALZHEIMER DISEASE BRAIN. An imbalance of neurotransmission has been proposed to cause the behavioral symptoms in Alzheimer disease (AD). Changes causing this imbalance are not clear. We tested whether it might involve changes neurotransmitter reuptake by vesicular glutamate transporters (VGLUTs), excitatory amino acid transporters (EAATs), the vesicular acetylcholine transporter (VAChT), the serotonin reuptake transporter (SERT), or the dopamine reuptake transporter (DAT). We tested this in postmortem prefrontal cortex from 10 AD patients and 10 non-AD controls. Compared with controls, protein and mRNA levels of VGLUTs, EAAT1-3, VAChT, and SERT were reduced significantly in AD. Expression of DAT and catechol O-methyltransferase was unchanged. Reduced VGLUTs and EAATs may alter glutamatergic recycling, and reduced SERT could exacerbate depression in AD. The reduced VAChT expression could contribute to the recognized cholinergic deficit in AD. Altered neurotransmitter transporters likely contribute to neurotransmission dysfunction in AD and are potential therapeutic targets (Chen et al., 2011). BIPOLAR DISORDER UNALTERED FATTY ACID COMPOSITION IN BIPOLAR DISORDER BRAIN. Docosahexaenoic (DHA) and arachidonic acid (AA) are critical to brain function and are concentrated in synaptic membrane phospholipids. However, in postmortem BD frontal cortex, we did not find a significant concentration difference for either fatty acid from control, whether concentration was measured per brain gram wet weight or as percent of the total fatty acid concentration. Since we reported altered AA metabolizing enzymes in the postmortem BD brain, we predict that measuring AA kinetics with our PET method would show brain abnormalities in patients (Igarashi et al., 2010). EXCITOTOXICITY AND NEUROINFLAMMATORY MARKERS IN FRONTAL CORTEX FROM BIPOLAR DISORDER PATIENTS. Cognitive decline, symptom worsening and brain atrophy in bipolar disorder (BD) indicate disease progression, which may involve excitotoxicity and neuroinflammation. To test this, we measured expression of excitotoxicity and neuroinflammatory markers in postmortem frontal cortex from 10 BD patients and 10 controls. Tissue was matched for age, postmortem interval and pH. There were significantly lower protein and mRNA levels of N-methyl-D-aspartate receptors, NR-1 and NR-3A, and higher protein and mRNA levels of interleukin (IL)-1beta, the IL-1 receptor (IL-1R), myeloid differentiation factor 88, nuclear factor-kappa B subunits, and astroglial and microglial markers (glial fibrillary acidic protein, inducible nitric oxide synthase, c-fos and CD11b) in the BD cortex. These data are consistent with excitotoxicity and neuroinflammation in BD, with activation of the IL-R cascade. They may account for disease progression and be a target for future therapy (Rao et al., 2010). APOPTOSIS AND SYNAPTIC LOSS IN BIPOLAR DISORDER BRAIN Bipolar disorder (BD) is associated with progressive brain atrophy and cognitive decline. We related these changes to cell death and synaptic loss, as we reported increased protein and mRNA levels of pro-apoptotic factors Bax, BAD, caspase-9 and caspase-3) and decreased levels of anti-apoptotic factors (BDNF and Bcl-2) and of synaptic markers (synaptophysin and drebrin) in BD compared with control postmortem prefrontal cortex. These changes are similar to changes in Alzheimer disease, suggesting a basis for common therapeutic approaches (Kim et al., 2010). ALTERED ARACHIDONIC ACID CASCADE ENZYMES IN BIPOLAR DISORDER BRAIN. Mood stabilizers that are approved for treating bipolar disorder (BD), when given chronically to rats, decrease expression of markers of the brain arachidonic acid (AA) metabolic cascade, and reduce excitotoxicity and neuroinflammation-induced upregulation of these markers. We therefore hypothesized that that AA metabolic markers are upregulated in the BD brain, and measured these markers in postmortem frontal cortex from 10 BD patients and 10 age-matched controls. Protein and mRNA levels of AA-selective cytosolic phospholipase A2 (cPLA2) IVA, secretory sPLA2 IIA, cyclooxygenase (COX)-2, and membrane prostaglandin E synthase (mPGES) were elevated, whereas levels of COX-1 and cytosolic PGES (cPGES) were reduced relative to controls, in BD cortex. These results confirm that enzymes associated with AA release from membrane phospholipid and with its downstream metabolism are upregulated in BD, and may explain why mood stabilizers that downregulate enzymes in animal model are clinically effective. An upregulated cascade should be considered as a target for drug development and for neuroimaging in BD (Kim et al., 2011). NEUROINFLAMMATION AND EXCITOTOXICITY IN BIPOLAR DISORDER. In a review of bipolar disorder (BD), we indicated how disease progression is related to neuroinflammation and excitotoxicity, and an upregulated brain arachidonic acid (AA) cascade. As similar changes occur in Alzheimer disease, antiinflammatory-antiexcitotoxicity therapies might be considered for both disorders (Rao et al, 2010).
2 Resulting Publications
Jagadeesh S Rao; Matthew Kellom; Hyung-Wook Kim; Stanley I Rapoport; Edmund A ReeseNeurochemical research 2012;37(5):903-10.
Pieter Stolk; Patrick C Souverein; Ingeborg Wilting; Hubert G M Leufkens; Donald F Klein; Stanley I Rapoport; Eibert R HeerdinkProstaglandins, leukotrienes, and essential fatty acids 2010;82(1):9-14.
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