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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 prevents hyperactivity, abnormal anxiety/exploration-related behavior, and premature mortality in hAPP mice. a–g, Mice (n=8−15 mice per genotype, age: 4−6 months) were tested in the open field (a,b), the Y maze (c,d), and the elevated plus maze (e–g). Genotype effects and interactions were assessed by two-way ANOVA. a, Total movements (P<0.001 for hAPP effect, P<0.0001 for PLA2 effect, P<0.01 for interaction). b, Total rearings (P<0.001 for hAPP effect, P<0.05 for PLA2 effect, and P<0.05 for interaction). c, Total entries (P<0.05 for hAPP effect, P<0.0001 for PLA2 effect, and P<0.001 for interaction). d, Total alternations (P<0.0001 for hAPP effect, P<0.001 for PLA2 effect, and P<0.0001 for interaction). (e) Percent time spent in open arms (P<0.0001 for hAPP effect, P<0.05 for PLA2 effect, and P=0.259 for interaction). (f) Percent distance traveled in open arms (P<0.0001 for hAPP effect, P<0.05 for PLA2 effect, P=0.237 for interaction). g, Edge pokes (P<0.0001 for hAPP effect, P<0.01 for PLA2 effect, P=0.133 for interaction). *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs. PLA2+/+ mice or as indicated by brackets (Dunnett test, mean ± s.e.m.). h, Kaplan-Meier survival analysis of 189 mice revealed premature mortality in hAPP/PLA2+/+ mice (P<0.001 by log-rank chi-square test), but not in hAPP/PLA2+/− or hAPP/PLA2−/− mice.
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Figure 5: GIVA-PLA2 reduction prevents hyperactivity, abnormal anxiety/exploration-related behavior, and premature mortality in hAPP mice. a–g, Mice (n=8−15 mice per genotype, age: 4−6 months) were tested in the open field (a,b), the Y maze (c,d), and the elevated plus maze (e–g). Genotype effects and interactions were assessed by two-way ANOVA. a, Total movements (P<0.001 for hAPP effect, P<0.0001 for PLA2 effect, P<0.01 for interaction). b, Total rearings (P<0.001 for hAPP effect, P<0.05 for PLA2 effect, and P<0.05 for interaction). c, Total entries (P<0.05 for hAPP effect, P<0.0001 for PLA2 effect, and P<0.001 for interaction). d, Total alternations (P<0.0001 for hAPP effect, P<0.001 for PLA2 effect, and P<0.0001 for interaction). (e) Percent time spent in open arms (P<0.0001 for hAPP effect, P<0.05 for PLA2 effect, and P=0.259 for interaction). (f) Percent distance traveled in open arms (P<0.0001 for hAPP effect, P<0.05 for PLA2 effect, P=0.237 for interaction). g, Edge pokes (P<0.0001 for hAPP effect, P<0.01 for PLA2 effect, P=0.133 for interaction). *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs. PLA2+/+ mice or as indicated by brackets (Dunnett test, mean ± s.e.m.). h, Kaplan-Meier survival analysis of 189 mice revealed premature mortality in hAPP/PLA2+/+ mice (P<0.001 by log-rank chi-square test), but not in hAPP/PLA2+/− or hAPP/PLA2−/− mice.

Mentions: hAPP mice demonstrate hyperactivity that may be related to memory deficits and entorhinal cortex dysfunction14, 15. Complete or partial removal of GIVA-PLA2 significantly decreased hyperactivity in hAPP mice, as reflected in the open field test (Fig. 5a,b) and the Y-maze (Fig. 5c,d). hAPP mice also show a disinhibition-like phenotype in the elevated plus maze, which is widely used to assess anxiety and exploratory behavior14, 15. Both PLA2 and hAPP genotype significantly affected elevated plus maze performance (Fig. 5e–g). Reduction of GIVA-PLA2 dose-dependently diminished the time spent (Fig. 5e) and distance traveled (Fig. 5f) in the open arms of the maze and the number of edge pokes (Fig. 5g) in hAPP mice. In mice without hAPP, removal of GIVA-PLA2 had much more subtle or no effects on these behaviors (Fig. 5a–g).


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 prevents hyperactivity, abnormal anxiety/exploration-related behavior, and premature mortality in hAPP mice. a–g, Mice (n=8−15 mice per genotype, age: 4−6 months) were tested in the open field (a,b), the Y maze (c,d), and the elevated plus maze (e–g). Genotype effects and interactions were assessed by two-way ANOVA. a, Total movements (P<0.001 for hAPP effect, P<0.0001 for PLA2 effect, P<0.01 for interaction). b, Total rearings (P<0.001 for hAPP effect, P<0.05 for PLA2 effect, and P<0.05 for interaction). c, Total entries (P<0.05 for hAPP effect, P<0.0001 for PLA2 effect, and P<0.001 for interaction). d, Total alternations (P<0.0001 for hAPP effect, P<0.001 for PLA2 effect, and P<0.0001 for interaction). (e) Percent time spent in open arms (P<0.0001 for hAPP effect, P<0.05 for PLA2 effect, and P=0.259 for interaction). (f) Percent distance traveled in open arms (P<0.0001 for hAPP effect, P<0.05 for PLA2 effect, P=0.237 for interaction). g, Edge pokes (P<0.0001 for hAPP effect, P<0.01 for PLA2 effect, P=0.133 for interaction). *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs. PLA2+/+ mice or as indicated by brackets (Dunnett test, mean ± s.e.m.). h, Kaplan-Meier survival analysis of 189 mice revealed premature mortality in hAPP/PLA2+/+ mice (P<0.001 by log-rank chi-square test), but not in hAPP/PLA2+/− or hAPP/PLA2−/− mice.
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Related In: Results  -  Collection

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Figure 5: GIVA-PLA2 reduction prevents hyperactivity, abnormal anxiety/exploration-related behavior, and premature mortality in hAPP mice. a–g, Mice (n=8−15 mice per genotype, age: 4−6 months) were tested in the open field (a,b), the Y maze (c,d), and the elevated plus maze (e–g). Genotype effects and interactions were assessed by two-way ANOVA. a, Total movements (P<0.001 for hAPP effect, P<0.0001 for PLA2 effect, P<0.01 for interaction). b, Total rearings (P<0.001 for hAPP effect, P<0.05 for PLA2 effect, and P<0.05 for interaction). c, Total entries (P<0.05 for hAPP effect, P<0.0001 for PLA2 effect, and P<0.001 for interaction). d, Total alternations (P<0.0001 for hAPP effect, P<0.001 for PLA2 effect, and P<0.0001 for interaction). (e) Percent time spent in open arms (P<0.0001 for hAPP effect, P<0.05 for PLA2 effect, and P=0.259 for interaction). (f) Percent distance traveled in open arms (P<0.0001 for hAPP effect, P<0.05 for PLA2 effect, P=0.237 for interaction). g, Edge pokes (P<0.0001 for hAPP effect, P<0.01 for PLA2 effect, P=0.133 for interaction). *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs. PLA2+/+ mice or as indicated by brackets (Dunnett test, mean ± s.e.m.). h, Kaplan-Meier survival analysis of 189 mice revealed premature mortality in hAPP/PLA2+/+ mice (P<0.001 by log-rank chi-square test), but not in hAPP/PLA2+/− or hAPP/PLA2−/− mice.
Mentions: hAPP mice demonstrate hyperactivity that may be related to memory deficits and entorhinal cortex dysfunction14, 15. Complete or partial removal of GIVA-PLA2 significantly decreased hyperactivity in hAPP mice, as reflected in the open field test (Fig. 5a,b) and the Y-maze (Fig. 5c,d). hAPP mice also show a disinhibition-like phenotype in the elevated plus maze, which is widely used to assess anxiety and exploratory behavior14, 15. Both PLA2 and hAPP genotype significantly affected elevated plus maze performance (Fig. 5e–g). Reduction of GIVA-PLA2 dose-dependently diminished the time spent (Fig. 5e) and distance traveled (Fig. 5f) in the open arms of the maze and the number of edge pokes (Fig. 5g) in hAPP mice. In mice without hAPP, removal of GIVA-PLA2 had much more subtle or no effects on these behaviors (Fig. 5a–g).

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