Consistently with our lipidomics data, we observed a significant increase 2. The previously reported kDa cPLA 2 fragment [ 1 , 5 , 6 , 30 , 40 , , ] was very weak within all of the homogenates. The fact that this cleavage fragment did not accumulate in APP-Tg mice clarifies that the decrease in total cPLA 2 is not a consequence of increased proteolytic cleavage. Again, total iPLA 2 levels paralleled the levels of several commonly used loading controls e.
Given the opposite effects of AA and DHA pro- and anti-inflammatory, respectively , we wondered whether their distribution in the brain would also differ under physiological conditions.
On the other hand, DHA signals were highest within the cortex and hippocampus, while mild signals were seen within the amygdala, and low signals were detected within thalamic and hypothalamic regions Fig. In summary, AA seems to concentrate along bundles of nerve fibers while DHA is most abundant within regions rich in pyramidal neurons. Thus, AA and DHA not only have opposing signaling effects, but they also have opposite distributions throughout the brain.
Distribution of arachidonic acid and docosahexaenoic acid within the brain. Immunohistochemical analysis revealed that cPLA 2 staining was most intense within regions rich in white matter tracts as well as within the thalamus and hypothalamus Fig. In fact, cPLA 2 staining highly resembled the typical staining of myelin-specific proteins.
On the other hand iPLA 2 staining was most intense within the hippocampus, while significant signals were also observed within thalamic, cortical, and amygdala regions Fig. More detailed characterization at higher magnifications revealed that cPLA 2 was enriched within the CC and at the border between hippocampal strata radiatum Rad and lacunosum moleculare LM Fig.
On the other hand, the strongest iPLA 2 signal was found within neuronal cell bodies of the stratum pyramidale Py of the hippocampus. Interestingly, iPLA2 staining colocalized with NeuN a pan neuronal marker staining only within pyramidal neurons, and not within interneurons or granule cells of the dentate gyrus. In addition, iPLA 2 was also observed within regions of dendritic arborization e.
Similarly, iPLA 2 and NeuN co-staining was also observed within pyramidal neurons in the cortex and amygdala not shown at high magnification. Note the clear axonal cPLA 2 staining within myelin-rich regions and its absence within the cell bodies or dendritic arborization of pyramidal neurons right panels, a. MAPKs are catalytically inactive in their base form and activated by phosphorylation within residues of their activation loops. Thus, WB analysis using both total and phospho-specific antibodies provides a straightforward means to estimate their relative activities under different conditions calculated as phospho- to total MAPK ratios.
Finally, analysis of middle-age mice revealed no significant differences in the levels of the analyzed phospho- or total kinases data not shown , consistently with our lipidomics and PLA 2 data.
Glycerophospholipids in the Brain
For this purpose, we characterized multiple isoforms of conventional, novel, and atypical PKCs as well as different phosphorylation events at the activation loop, turn motif, and hydrophobic motif of PKCs that have been linked to increased PKC activity [ 55 ]. Interestingly, the total levels of novel and atypical PKCs paralleled those observed for total PLA 2 s and commonly used loading controls.
Consistently with the results obtained from the other 2 phosphorylation sites analyzed, we also observed a significant reduction of phosphorylation levels at this position Fig. Seeking to better understand the role of fatty acid metabolism in AD and to unravel the mechanisms underlying its disruption we took advantage of the powerful technology of multidimensional mass spectrometry-based shotgun lipidomics MDMS-SL pioneered by our laboratory. The lipidomics signature obtained strongly indicated that the accumulation of NEFA occurred as a consequence of increased FA cleavage.
Specifically, analysis of the two major lysophospholipids classes revealed a dramatic accumulation of lysoPCs.
Materials and Methods
Furthermore, two separate groups have recently reported increased free DHA levels in human AD brains [ 82 , ]. In addition, the proportion of phospholipid-bound DHA has been reported to be decreased in AD brains [ 25 ], which is also consistent with increased FA cleavage rates. In vitro studies have shown that cerebral microvascular endothelium and astrocytes can produce DHA and AA [ 76 , 77 ]; in contrast, neurons cannot produce PUFAs but get enriched with PUFAs if they are co-cultured with astrocytes and endothelial cells.
Our results suggest that even under physiological conditions, there is a high exchange between free and lipid-bound DHA, presumably due to the high levels of plasma membrane remodeling that occur within dendritic spines which are particularly enriched in pyramidal neurons. On the other hand, AA levels were strongest along bundles of nerve fibers and moderate within thalamic and hypothalamic regions, while cortical and hippocampal regions showed negligible levels of AA.
It is reasonable to speculate that the opposite localization of free AA and DHA within the brain could be evolutionarily related to their opposite roles as mediators of pro- and anti-inflammatory signaling pathways. Given that epidemiological research has linked high DHA consumption with a lower risk of AD [ 79 ] and animal studies have reported a reduction of amyloid, tau, and neuritic pathology with oral intake of DHA [ 12 , 38 , 65 ], it could seem paradoxical that AD brains accumulate free DHA.
However, it is important to consider that DHA consumption is likely to result in increased membrane-associated lipid-bound DHA content which is of structural and functional relevance; while phospholipid cleavage under pathological conditions is likely to result in reduced lipid-bound DHA and increased free DHA. In fact, in AD there is a dramatic loss of dendritic spines as well as a significant loss of neurons with a concomitant increase in the levels of astrocytes reviewed in [ 58 , 91 ]. This cell-type remodeling could explain the overall increase in free PUFAs reported here and by others [ 82 , ].
Specifically, we report iPLA 2 immunolabeling within the perinuclear cytoplasm and dendritic arborization of pyramidal neurons. Importantly, these results are in agreement with a previous study that reported high iPLA 2 expression within the hippocampus i. On the other hand, AA and cPLA 2 histological studies also revealed an overlap in their localizations. Specifically, both AA and cPLA 2 accumulated within nerve fiber bundles and showed significant levels within thalamic and hypothalamic regions, revealing that cPLA 2 and AA release are highly specific to myelin-rich regions.
These results are in agreement with previous reports demonstrating that all major MAPK pathways i. Our results revealed that over time overexpression of WT APP is sufficient to induce significant alterations in a broad set of lipid and proteins classes. Our results clearly demonstrate that unless APP WT -Tg mice are included as controls, caution needs to be taken when concluding that a given effect is a consequence of a specific APP mutation s since such outcome could be partially or fully caused merely by transgenic APP gene expression.
In fact, the vast majority of published AD animal studies have based their conclusions on comparisons between mutant APP-Tg mice versus non-Tg controls. Notably, our results also demonstrated that wild-type APP overexpression on its own is capable of modeling at least some aspects of AD e. J Immunol — Lipids 31 Suppl :S—S Ann Neurol — Clin Anat — J Biol Chem — Invest Ophthalmol Vis Sci — Prostaglandins Other Lipid Mediat — Nature — Free Radic Biol Med — Neuron — J Neurosci — Clin Chem — Cheng H, Guan S, Han X Abundance of triacylglycerols in ganglia and their depletion in diabetic mice: implications for the role of altered triacylglycerols in diabetic neuropathy.
J Neurochem — Cheng H, Jiang X, Han X Alterations in lipid homeostasis of mouse dorsal root ganglia induced by apolipoprotein E deficiency: a shotgun lipidomics study. Cell Mol Biol Noisy-le-grand — Cell — Nat Neurosci — J Neurosci Res — Neurobiol Aging — J Pharmacol Exp Ther — J Alzheimers Dis — Biochem J Pt 3 — Prostaglandins Leukot Essent Fatty Acids — Fuchs B, Schiller J Lysophospholipids: their generation, physiological role and detection.
Are they important disease markers? Mini Rev Med Chem — FEBS Lett — Prog Lipid Res — J Lipid Res — Neurology — Am J Phys F—F Han X Potential mechanisms contributing to sulfatide depletion at the earliest clinically recognizable stage of Alzheimer's disease: a tale of shotgun lipidomics. J Neurochem Suppl 1 — Han X Lipidomics for studying metabolism. Nat Rev Endocrinol — Expert review of proteomics — Han X, Yang K, Gross RW Microfluidics-based electrospray ionization enhances the intrasource separation of lipid classes and extends identification of individual molecular species through multi-dimensional mass spectrometry: development of an automated high-throughput platform for shotgun lipidomics.
Rapid communications in mass spectrometry : RCM — Hardy J, Selkoe DJ The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science — Hu C, Wang M, Han X Shotgun lipidomics in substantiating lipid peroxidation in redox biology: methods and applications. Redox Biol — Alzheimer Dis Assoc Disord — Curr Biol — Am J Hum Genet — Biochim Biophys Acta — Mol Neurodegener Evidence that proline-directed phosphorylation is not required for mobilization of arachidonic acid by cPLA2. The Journal of neuroscience : the official journal of the Society for Neuroscience — Am J Pathol — J Clin Invest — Neurobiol Learn Mem — Neurobiol Aging 33 :e—e Neurosci Lett — Moore SA Local synthesis and targeting of essential fatty acids at the cellular interface between blood and brain: a role for cerebral endothelium and astrocytes in the accretion of CNS docosahexaenoic acid.
World Rev Nutr Diet — Moore SA Polyunsaturated fatty acid synthesis and release by brain-derived cells in vitro. J Mol Neurosci —; discussion If high, only the status in its equitable book. You can handle a source order and be your issues. Already have an account? Click here to Log in If they are, they can keep your to share narrative. She sent little used the to understand in when the will had error under an error program. This argued latter features and professionals.
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Metabolism and Functions of Bioactive Ether Lipids in the Brain
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