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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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GIVA-PLA2 reduction improves learning and memory in hAPP mice. a,b, Mice (n=8−15 per genotype; age: 4−6 months) were tested in the cued (a) and hidden (b) platform components of the Morris water maze. In both components, hAPP/PLA2+/+ mice differed from all groups without hAPP (P<0.0001, by repeated-measures ANOVA and Tukey test). In the hidden platform component, hAPP/PLA2+/+ mice learned more poorly than hAPP/PLA2+/− mice (P<0.05) and hAPP/PLA2−/− mice (P<0.01, by repeated-measures ANOVA and Tukey test). c, Representative swim paths of individual mice with indicated genotypes during the last probe trial (platform removed). The blue square indicates the target location during hidden platform training. d, Number of times mice crossed this target location during the last probe trial compared with how many times they crossed corresponding locations in non-target quadrants. Only hAPP/PLA2+/+ mice failed to show a clear target location preference. A two-way ANOVA of target/nontarget ratios revealed significant effects of hAPP (P<0.0001) and PLA2 (P<0.001) and a significant interaction between hAPP and PLA2 genotype (P<0.001). *P<0.05, **P<0.01, ***P<0.001 vs. nontarget locations; ###P<0.001 (Tukey test, mean ± s.e.m.).
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Figure 4: GIVA-PLA2 reduction improves learning and memory in hAPP mice. a,b, Mice (n=8−15 per genotype; age: 4−6 months) were tested in the cued (a) and hidden (b) platform components of the Morris water maze. In both components, hAPP/PLA2+/+ mice differed from all groups without hAPP (P<0.0001, by repeated-measures ANOVA and Tukey test). In the hidden platform component, hAPP/PLA2+/+ mice learned more poorly than hAPP/PLA2+/− mice (P<0.05) and hAPP/PLA2−/− mice (P<0.01, by repeated-measures ANOVA and Tukey test). c, Representative swim paths of individual mice with indicated genotypes during the last probe trial (platform removed). The blue square indicates the target location during hidden platform training. d, Number of times mice crossed this target location during the last probe trial compared with how many times they crossed corresponding locations in non-target quadrants. Only hAPP/PLA2+/+ mice failed to show a clear target location preference. A two-way ANOVA of target/nontarget ratios revealed significant effects of hAPP (P<0.0001) and PLA2 (P<0.001) and a significant interaction between hAPP and PLA2 genotype (P<0.001). *P<0.05, **P<0.01, ***P<0.001 vs. nontarget locations; ###P<0.001 (Tukey test, mean ± s.e.m.).

Mentions: To determine if GIVA-PLA2 contributes to Aβ-dependent behavioral deficits in vivo, we bred hAPP and NTG mice with GIVA-PLA2-deficient mice to generate six genotypes: hAPP/PLA2+/+, hAPP/PLA2+/−, hAPP/PLA2−/−, PLA2+/+, PLA2+/−, and PLA2−/−. These groups did not differ in background strain, body weight, gross motor function, or swim speed (Supplementary Fig. 11). Removal or reduction of GIVA-PLA2 significantly reduced hippocampal levels of AA and its metabolites in hAPP mice (Supplementary Figure 12). To determine if these changes ameliorated cognitive deficits in hAPP mice, we tested the above groups in the Morris water maze. In the cued component of this test, hAPP mice exhibited deficits in task acquisition that were independent of GIVA-PLA2 levels (Fig. 4a). In the hidden platform (spatial) component of the test, complete or partial removal of GIVA-PLA2 reduced learning deficits in hAPP mice (Fig. 4b). In the probe trial, a putative measure of spatial learning and memory retention, only hAPP/PLA2+/+ mice failed to favor the target platform location (Fig. 4c,d). Removal or reduction of GIVA-PLA2 significantly improved target crossings in hAPP mice in the probe trial (Fig. 4c,d). In addition, hAPP mice with GIVA-PLA2 reduction or removal showed a trend for improved overall target quadrant preference during the final probe trial (data not shown).


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)

GIVA-PLA2 reduction improves learning and memory in hAPP mice. a,b, Mice (n=8−15 per genotype; age: 4−6 months) were tested in the cued (a) and hidden (b) platform components of the Morris water maze. In both components, hAPP/PLA2+/+ mice differed from all groups without hAPP (P<0.0001, by repeated-measures ANOVA and Tukey test). In the hidden platform component, hAPP/PLA2+/+ mice learned more poorly than hAPP/PLA2+/− mice (P<0.05) and hAPP/PLA2−/− mice (P<0.01, by repeated-measures ANOVA and Tukey test). c, Representative swim paths of individual mice with indicated genotypes during the last probe trial (platform removed). The blue square indicates the target location during hidden platform training. d, Number of times mice crossed this target location during the last probe trial compared with how many times they crossed corresponding locations in non-target quadrants. Only hAPP/PLA2+/+ mice failed to show a clear target location preference. A two-way ANOVA of target/nontarget ratios revealed significant effects of hAPP (P<0.0001) and PLA2 (P<0.001) and a significant interaction between hAPP and PLA2 genotype (P<0.001). *P<0.05, **P<0.01, ***P<0.001 vs. nontarget locations; ###P<0.001 (Tukey test, mean ± s.e.m.).
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Figure 4: GIVA-PLA2 reduction improves learning and memory in hAPP mice. a,b, Mice (n=8−15 per genotype; age: 4−6 months) were tested in the cued (a) and hidden (b) platform components of the Morris water maze. In both components, hAPP/PLA2+/+ mice differed from all groups without hAPP (P<0.0001, by repeated-measures ANOVA and Tukey test). In the hidden platform component, hAPP/PLA2+/+ mice learned more poorly than hAPP/PLA2+/− mice (P<0.05) and hAPP/PLA2−/− mice (P<0.01, by repeated-measures ANOVA and Tukey test). c, Representative swim paths of individual mice with indicated genotypes during the last probe trial (platform removed). The blue square indicates the target location during hidden platform training. d, Number of times mice crossed this target location during the last probe trial compared with how many times they crossed corresponding locations in non-target quadrants. Only hAPP/PLA2+/+ mice failed to show a clear target location preference. A two-way ANOVA of target/nontarget ratios revealed significant effects of hAPP (P<0.0001) and PLA2 (P<0.001) and a significant interaction between hAPP and PLA2 genotype (P<0.001). *P<0.05, **P<0.01, ***P<0.001 vs. nontarget locations; ###P<0.001 (Tukey test, mean ± s.e.m.).
Mentions: To determine if GIVA-PLA2 contributes to Aβ-dependent behavioral deficits in vivo, we bred hAPP and NTG mice with GIVA-PLA2-deficient mice to generate six genotypes: hAPP/PLA2+/+, hAPP/PLA2+/−, hAPP/PLA2−/−, PLA2+/+, PLA2+/−, and PLA2−/−. These groups did not differ in background strain, body weight, gross motor function, or swim speed (Supplementary Fig. 11). Removal or reduction of GIVA-PLA2 significantly reduced hippocampal levels of AA and its metabolites in hAPP mice (Supplementary Figure 12). To determine if these changes ameliorated cognitive deficits in hAPP mice, we tested the above groups in the Morris water maze. In the cued component of this test, hAPP mice exhibited deficits in task acquisition that were independent of GIVA-PLA2 levels (Fig. 4a). In the hidden platform (spatial) component of the test, complete or partial removal of GIVA-PLA2 reduced learning deficits in hAPP mice (Fig. 4b). In the probe trial, a putative measure of spatial learning and memory retention, only hAPP/PLA2+/+ mice failed to favor the target platform location (Fig. 4c,d). Removal or reduction of GIVA-PLA2 significantly improved target crossings in hAPP mice in the probe trial (Fig. 4c,d). In addition, hAPP mice with GIVA-PLA2 reduction or removal showed a trend for improved overall target quadrant preference during the final probe trial (data not shown).

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