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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 levels in hAPP mice and humans with AD. (a–f) Coronal sections of cortex and hippocampus (a–c) or hippocampus (d–f) in 6-month-old NTG (a,d), hAPP (b,e), and GIVA-PLA2-deficient (c,f) mice. Scale bar (a–c) 1 mm, (d–f) 250 μm. g–i, Hippocampal and cortical levels of GIVA-PLA2 in mice were determined by western blot analysis with a rabbit polyclonal antibody. g, Representative western blot showing levels of phosphorylated (p) and unphosphorylated (u) GIVA-PLA2. Tubulin served as a loading control, NIH3T3 cells as a positive control (+), and cortex from GIVA-PLA2-deficient mice as a negative control (−). h,i, Hippocampal (h) and cortical (i) GIVA-PLA2 levels determined by densitometric analysis of western blot signals (n=12 mice per genotype and brain region; age: 6 months). j, hAPP mRNA levels in hippocampus and cortex of hAPP mice determined by quantitative RT-PCR (n=7 mice; age: 2−4 months). k, l, Levels of Aβ1-x (k) and Aβ1−42 (l) (ng per g of tissue) in hippocampus and cortex of hAPP mice determined by ELISA (n=8 mice; age, 2−4 months). m–n, Levels of phosphorylated GIVA-PLA2 protein in the CA1 hippocampal region in patients with mild, moderate, or severe AD and in nondemented, age-matched controls (C) were determined by western blot analysis. m, Representative western blot. n, Western blot signals were quantitated densitometrically and normalized to tubulin (n=4−8 cases per group). *P<0.05, ****P<0.0001 (t test; mean ± s.e.m.), **P<0.01 vs. control (Tukey test; mean ± s.e.m.).
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Figure 2: GIVA-PLA2 levels in hAPP mice and humans with AD. (a–f) Coronal sections of cortex and hippocampus (a–c) or hippocampus (d–f) in 6-month-old NTG (a,d), hAPP (b,e), and GIVA-PLA2-deficient (c,f) mice. Scale bar (a–c) 1 mm, (d–f) 250 μm. g–i, Hippocampal and cortical levels of GIVA-PLA2 in mice were determined by western blot analysis with a rabbit polyclonal antibody. g, Representative western blot showing levels of phosphorylated (p) and unphosphorylated (u) GIVA-PLA2. Tubulin served as a loading control, NIH3T3 cells as a positive control (+), and cortex from GIVA-PLA2-deficient mice as a negative control (−). h,i, Hippocampal (h) and cortical (i) GIVA-PLA2 levels determined by densitometric analysis of western blot signals (n=12 mice per genotype and brain region; age: 6 months). j, hAPP mRNA levels in hippocampus and cortex of hAPP mice determined by quantitative RT-PCR (n=7 mice; age: 2−4 months). k, l, Levels of Aβ1-x (k) and Aβ1−42 (l) (ng per g of tissue) in hippocampus and cortex of hAPP mice determined by ELISA (n=8 mice; age, 2−4 months). m–n, Levels of phosphorylated GIVA-PLA2 protein in the CA1 hippocampal region in patients with mild, moderate, or severe AD and in nondemented, age-matched controls (C) were determined by western blot analysis. m, Representative western blot. n, Western blot signals were quantitated densitometrically and normalized to tubulin (n=4−8 cases per group). *P<0.05, ****P<0.0001 (t test; mean ± s.e.m.), **P<0.01 vs. control (Tukey test; mean ± s.e.m.).

Mentions: GIVA-PLA2 immunoreactivity was readily detectable in brains of our hAPP mice and NTG controls. Immunostaining with a GIVA-PLA2-specific antibody resulted in a comparable widespread neuronal labeling in brain sections from NTG and hAPP mice on the wildtype GIVA-PLA2 background (Fig. 2a,b), with dense labeling of granule cells of the dentate gyrus and pyramidal neurons in the CA1−3 regions (Fig. 2d,e). No staining was seen in GIVA-PLA2-deficient mice (Fig. 2c,f). Our findings are consistent with detection of neuronal GIVA-PLA2 mRNA25 and immunoreactivity26 in rats.


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 levels in hAPP mice and humans with AD. (a–f) Coronal sections of cortex and hippocampus (a–c) or hippocampus (d–f) in 6-month-old NTG (a,d), hAPP (b,e), and GIVA-PLA2-deficient (c,f) mice. Scale bar (a–c) 1 mm, (d–f) 250 μm. g–i, Hippocampal and cortical levels of GIVA-PLA2 in mice were determined by western blot analysis with a rabbit polyclonal antibody. g, Representative western blot showing levels of phosphorylated (p) and unphosphorylated (u) GIVA-PLA2. Tubulin served as a loading control, NIH3T3 cells as a positive control (+), and cortex from GIVA-PLA2-deficient mice as a negative control (−). h,i, Hippocampal (h) and cortical (i) GIVA-PLA2 levels determined by densitometric analysis of western blot signals (n=12 mice per genotype and brain region; age: 6 months). j, hAPP mRNA levels in hippocampus and cortex of hAPP mice determined by quantitative RT-PCR (n=7 mice; age: 2−4 months). k, l, Levels of Aβ1-x (k) and Aβ1−42 (l) (ng per g of tissue) in hippocampus and cortex of hAPP mice determined by ELISA (n=8 mice; age, 2−4 months). m–n, Levels of phosphorylated GIVA-PLA2 protein in the CA1 hippocampal region in patients with mild, moderate, or severe AD and in nondemented, age-matched controls (C) were determined by western blot analysis. m, Representative western blot. n, Western blot signals were quantitated densitometrically and normalized to tubulin (n=4−8 cases per group). *P<0.05, ****P<0.0001 (t test; mean ± s.e.m.), **P<0.01 vs. control (Tukey test; mean ± s.e.m.).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2597064&req=5

Figure 2: GIVA-PLA2 levels in hAPP mice and humans with AD. (a–f) Coronal sections of cortex and hippocampus (a–c) or hippocampus (d–f) in 6-month-old NTG (a,d), hAPP (b,e), and GIVA-PLA2-deficient (c,f) mice. Scale bar (a–c) 1 mm, (d–f) 250 μm. g–i, Hippocampal and cortical levels of GIVA-PLA2 in mice were determined by western blot analysis with a rabbit polyclonal antibody. g, Representative western blot showing levels of phosphorylated (p) and unphosphorylated (u) GIVA-PLA2. Tubulin served as a loading control, NIH3T3 cells as a positive control (+), and cortex from GIVA-PLA2-deficient mice as a negative control (−). h,i, Hippocampal (h) and cortical (i) GIVA-PLA2 levels determined by densitometric analysis of western blot signals (n=12 mice per genotype and brain region; age: 6 months). j, hAPP mRNA levels in hippocampus and cortex of hAPP mice determined by quantitative RT-PCR (n=7 mice; age: 2−4 months). k, l, Levels of Aβ1-x (k) and Aβ1−42 (l) (ng per g of tissue) in hippocampus and cortex of hAPP mice determined by ELISA (n=8 mice; age, 2−4 months). m–n, Levels of phosphorylated GIVA-PLA2 protein in the CA1 hippocampal region in patients with mild, moderate, or severe AD and in nondemented, age-matched controls (C) were determined by western blot analysis. m, Representative western blot. n, Western blot signals were quantitated densitometrically and normalized to tubulin (n=4−8 cases per group). *P<0.05, ****P<0.0001 (t test; mean ± s.e.m.), **P<0.01 vs. control (Tukey test; mean ± s.e.m.).
Mentions: GIVA-PLA2 immunoreactivity was readily detectable in brains of our hAPP mice and NTG controls. Immunostaining with a GIVA-PLA2-specific antibody resulted in a comparable widespread neuronal labeling in brain sections from NTG and hAPP mice on the wildtype GIVA-PLA2 background (Fig. 2a,b), with dense labeling of granule cells of the dentate gyrus and pyramidal neurons in the CA1−3 regions (Fig. 2d,e). No staining was seen in GIVA-PLA2-deficient mice (Fig. 2c,f). Our findings are consistent with detection of neuronal GIVA-PLA2 mRNA25 and immunoreactivity26 in rats.

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