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Phospholipase A2 reduction ameliorates cognitive deficits in a mouse model of Alzheimer's disease.

Sanchez-Mejia RO, Newman JW, Toh S, Yu GQ, Zhou Y, Halabisky B, Cissé M, Scearce-Levie K, Cheng IH, Gan L, Palop JJ, Bonventre JV, Mucke L - Nat. Neurosci. (2008)

Bottom Line: We used a lipidomics approach to generate a broad profile of fatty acids in brain tissues of hAPP-expressing mice and found an increase in arachidonic acid and its metabolites, suggesting increased activity of the group IV isoform of phospholipase A(2) (GIVA-PLA(2)).Abeta caused a dose-dependent increase in GIVA-PLA(2) phosphorylation in neuronal cultures.Inhibition of GIVA-PLA(2) diminished Abeta-induced neurotoxicity.

View Article: PubMed Central - PubMed

Affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA. rene_sanchez@post.harvard.edu

ABSTRACT
Neuronal expression of familial Alzheimer's disease-mutant human amyloid precursor protein (hAPP) and hAPP-derived amyloid-beta (Abeta) peptides causes synaptic dysfunction, inflammation and abnormal cerebrovascular tone in transgenic mice. Fatty acids may be involved in these processes, but their contribution to Alzheimer's disease pathogenesis is uncertain. We used a lipidomics approach to generate a broad profile of fatty acids in brain tissues of hAPP-expressing mice and found an increase in arachidonic acid and its metabolites, suggesting increased activity of the group IV isoform of phospholipase A(2) (GIVA-PLA(2)). The levels of activated GIVA-PLA(2) in the hippocampus were increased in individuals with Alzheimer's disease and in hAPP mice. Abeta caused a dose-dependent increase in GIVA-PLA(2) phosphorylation in neuronal cultures. Inhibition of GIVA-PLA(2) diminished Abeta-induced neurotoxicity. Genetic ablation or reduction of GIVA-PLA(2) protected hAPP mice against Abeta-dependent deficits in learning and memory, behavioral alterations and premature mortality. Inhibition of GIVA-PLA(2) may be beneficial in the treatment and prevention of Alzheimer's disease.

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Increased PLA2-dependent fatty acid levels in brain tissues of hAPP mice. Lipids were extracted from hippocampal or cortical homogenates from hAPP and NTG mice (n=12 per genotype) and analyzed by quantitative LC-MS/MS. Fatty acid levels (pmol) were normalized to total protein (mg). a–f, Hippocampal and cortical levels of (a) AA, (b) total AA-derived metabolites, (c) PGE2 and its nonenzymatic PGB2 degradation product, (d) LTB4, (e) 14,15-EET and its 14,15-DHET metabolite, and (f) total fatty acids. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs. NTG or as indicated by bracket (t test; means ± s.e.m.).
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Figure 1: Increased PLA2-dependent fatty acid levels in brain tissues of hAPP mice. Lipids were extracted from hippocampal or cortical homogenates from hAPP and NTG mice (n=12 per genotype) and analyzed by quantitative LC-MS/MS. Fatty acid levels (pmol) were normalized to total protein (mg). a–f, Hippocampal and cortical levels of (a) AA, (b) total AA-derived metabolites, (c) PGE2 and its nonenzymatic PGB2 degradation product, (d) LTB4, (e) 14,15-EET and its 14,15-DHET metabolite, and (f) total fatty acids. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs. NTG or as indicated by bracket (t test; means ± s.e.m.).

Mentions: To profile essential fatty acid metabolism, we measured the levels of 44 pertinent metabolites in the hippocampus and cortex of transgenic mice with neuronal expression of familial AD-mutant hAPP (line J20, refs.2, 12-15) and nontransgenic (NTG) controls by simultaneous liquid chromatography–tandem triple–quadrupole mass spectrometry (LC-MS/MS) (Supplementary Fig. 1). Hippocampal levels of arachidonic acid (AA) were higher in hAPP mice than in NTG controls, whereas cortical AA levels were comparable (Fig. 1a). Total AA-derived metabolites were also increased in the hippocampus, but not cortex, of hAPP mice (Fig. 1b). Hippocampal, but not cortical, levels of prostaglandin (PG) E2 and PGB2 were higher in hAPP mice than in NTG mice (Fig. 1c). The increase in PGE2 is consistent with the increased hippocampal cyclooxygenase (COX)-2 in another hAPP transgenic model16. Both AA and PG regulate long-term potentiation (LTP)17, which is important for learning and memory. Excessive levels of AA and PG can contribute to excitotoxicity5, which may be involved in AD pathogenesis3, 12, 13. In addition, AA and PG contribute to inflammation, which may also contribute to AD1. Inflammation might be further promoted by leukotrienes (LT), AA-derived fatty acids that are potent chemoattractants for monocytes and granulocytes18. LTB4 levels were higher in hAPP mice than NTG controls in both the hippocampus and cortex (Fig. 1d). Increased LTB4 levels may contribute to the microgliosis seen in hAPP mice and AD patients.


Phospholipase A2 reduction ameliorates cognitive deficits in a mouse model of Alzheimer's disease.

Sanchez-Mejia RO, Newman JW, Toh S, Yu GQ, Zhou Y, Halabisky B, Cissé M, Scearce-Levie K, Cheng IH, Gan L, Palop JJ, Bonventre JV, Mucke L - Nat. Neurosci. (2008)

Increased PLA2-dependent fatty acid levels in brain tissues of hAPP mice. Lipids were extracted from hippocampal or cortical homogenates from hAPP and NTG mice (n=12 per genotype) and analyzed by quantitative LC-MS/MS. Fatty acid levels (pmol) were normalized to total protein (mg). a–f, Hippocampal and cortical levels of (a) AA, (b) total AA-derived metabolites, (c) PGE2 and its nonenzymatic PGB2 degradation product, (d) LTB4, (e) 14,15-EET and its 14,15-DHET metabolite, and (f) total fatty acids. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs. NTG or as indicated by bracket (t test; means ± s.e.m.).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2597064&req=5

Figure 1: Increased PLA2-dependent fatty acid levels in brain tissues of hAPP mice. Lipids were extracted from hippocampal or cortical homogenates from hAPP and NTG mice (n=12 per genotype) and analyzed by quantitative LC-MS/MS. Fatty acid levels (pmol) were normalized to total protein (mg). a–f, Hippocampal and cortical levels of (a) AA, (b) total AA-derived metabolites, (c) PGE2 and its nonenzymatic PGB2 degradation product, (d) LTB4, (e) 14,15-EET and its 14,15-DHET metabolite, and (f) total fatty acids. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs. NTG or as indicated by bracket (t test; means ± s.e.m.).
Mentions: To profile essential fatty acid metabolism, we measured the levels of 44 pertinent metabolites in the hippocampus and cortex of transgenic mice with neuronal expression of familial AD-mutant hAPP (line J20, refs.2, 12-15) and nontransgenic (NTG) controls by simultaneous liquid chromatography–tandem triple–quadrupole mass spectrometry (LC-MS/MS) (Supplementary Fig. 1). Hippocampal levels of arachidonic acid (AA) were higher in hAPP mice than in NTG controls, whereas cortical AA levels were comparable (Fig. 1a). Total AA-derived metabolites were also increased in the hippocampus, but not cortex, of hAPP mice (Fig. 1b). Hippocampal, but not cortical, levels of prostaglandin (PG) E2 and PGB2 were higher in hAPP mice than in NTG mice (Fig. 1c). The increase in PGE2 is consistent with the increased hippocampal cyclooxygenase (COX)-2 in another hAPP transgenic model16. Both AA and PG regulate long-term potentiation (LTP)17, which is important for learning and memory. Excessive levels of AA and PG can contribute to excitotoxicity5, which may be involved in AD pathogenesis3, 12, 13. In addition, AA and PG contribute to inflammation, which may also contribute to AD1. Inflammation might be further promoted by leukotrienes (LT), AA-derived fatty acids that are potent chemoattractants for monocytes and granulocytes18. LTB4 levels were higher in hAPP mice than NTG controls in both the hippocampus and cortex (Fig. 1d). Increased LTB4 levels may contribute to the microgliosis seen in hAPP mice and AD patients.

Bottom Line: We used a lipidomics approach to generate a broad profile of fatty acids in brain tissues of hAPP-expressing mice and found an increase in arachidonic acid and its metabolites, suggesting increased activity of the group IV isoform of phospholipase A(2) (GIVA-PLA(2)).Abeta caused a dose-dependent increase in GIVA-PLA(2) phosphorylation in neuronal cultures.Inhibition of GIVA-PLA(2) diminished Abeta-induced neurotoxicity.

View Article: PubMed Central - PubMed

Affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA. rene_sanchez@post.harvard.edu

ABSTRACT
Neuronal expression of familial Alzheimer's disease-mutant human amyloid precursor protein (hAPP) and hAPP-derived amyloid-beta (Abeta) peptides causes synaptic dysfunction, inflammation and abnormal cerebrovascular tone in transgenic mice. Fatty acids may be involved in these processes, but their contribution to Alzheimer's disease pathogenesis is uncertain. We used a lipidomics approach to generate a broad profile of fatty acids in brain tissues of hAPP-expressing mice and found an increase in arachidonic acid and its metabolites, suggesting increased activity of the group IV isoform of phospholipase A(2) (GIVA-PLA(2)). The levels of activated GIVA-PLA(2) in the hippocampus were increased in individuals with Alzheimer's disease and in hAPP mice. Abeta caused a dose-dependent increase in GIVA-PLA(2) phosphorylation in neuronal cultures. Inhibition of GIVA-PLA(2) diminished Abeta-induced neurotoxicity. Genetic ablation or reduction of GIVA-PLA(2) protected hAPP mice against Abeta-dependent deficits in learning and memory, behavioral alterations and premature mortality. Inhibition of GIVA-PLA(2) may be beneficial in the treatment and prevention of Alzheimer's disease.

Show MeSH
Related in: MedlinePlus