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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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Reduction or removal of GIVA-PLA2 did not affect hAPP or Aβ levels in hAPP mice. a, Hippocampal hAPP protein levels (relative to GADPH) in hAPP mice with different levels of GIVA-PLA2 expression (n=6 per group; age, 4−6 months) were determined by western blotting and densitometric analysis of signals. b–d, Hippocampal and cortical levels of Aβ1-x (b) and Aβ1−42 (c) and Aβ1−42/Aβ1-x ratios (d) in 4−6-month-old hAPP mice with different levels of GIVA-PLA2 expression (n=6−10 per group; age, 4−6 months) were determined by ELISA and expressed as ng per g of tissue.
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Figure 6: Reduction or removal of GIVA-PLA2 did not affect hAPP or Aβ levels in hAPP mice. a, Hippocampal hAPP protein levels (relative to GADPH) in hAPP mice with different levels of GIVA-PLA2 expression (n=6 per group; age, 4−6 months) were determined by western blotting and densitometric analysis of signals. b–d, Hippocampal and cortical levels of Aβ1-x (b) and Aβ1−42 (c) and Aβ1−42/Aβ1-x ratios (d) in 4−6-month-old hAPP mice with different levels of GIVA-PLA2 expression (n=6−10 per group; age, 4−6 months) were determined by ELISA and expressed as ng per g of tissue.

Mentions: hAPP mice also exhibit premature mortality (Fig. 5h), possibly related to their lowered seizure threshold12, 13, 15. Removal or reduction of GIVA-PLA2 significantly improved the survival of hAPP mice (Fig. 5h) without altering the levels of hAPP (Fig. 6a), Aβ1-x (Fig. 6b), Aβ1−42 (Fig. 6c), or the Aβ1−42/Aβ1-x ratio (Fig. 6d). Removal or reduction of GIVA-PLA2 also did not alter Aβ deposition, astroglial activation (GFAP immunostaining), or microglial numbers (Iba-1 immunostaining) (data not shown). These findings suggest that GIVA-PLA2 reduction blocks or counteracts AD-related abnormalities downstream of Aβ production and deposition.


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)

Reduction or removal of GIVA-PLA2 did not affect hAPP or Aβ levels in hAPP mice. a, Hippocampal hAPP protein levels (relative to GADPH) in hAPP mice with different levels of GIVA-PLA2 expression (n=6 per group; age, 4−6 months) were determined by western blotting and densitometric analysis of signals. b–d, Hippocampal and cortical levels of Aβ1-x (b) and Aβ1−42 (c) and Aβ1−42/Aβ1-x ratios (d) in 4−6-month-old hAPP mice with different levels of GIVA-PLA2 expression (n=6−10 per group; age, 4−6 months) were determined by ELISA and expressed as ng per g of tissue.
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Related In: Results  -  Collection

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Figure 6: Reduction or removal of GIVA-PLA2 did not affect hAPP or Aβ levels in hAPP mice. a, Hippocampal hAPP protein levels (relative to GADPH) in hAPP mice with different levels of GIVA-PLA2 expression (n=6 per group; age, 4−6 months) were determined by western blotting and densitometric analysis of signals. b–d, Hippocampal and cortical levels of Aβ1-x (b) and Aβ1−42 (c) and Aβ1−42/Aβ1-x ratios (d) in 4−6-month-old hAPP mice with different levels of GIVA-PLA2 expression (n=6−10 per group; age, 4−6 months) were determined by ELISA and expressed as ng per g of tissue.
Mentions: hAPP mice also exhibit premature mortality (Fig. 5h), possibly related to their lowered seizure threshold12, 13, 15. Removal or reduction of GIVA-PLA2 significantly improved the survival of hAPP mice (Fig. 5h) without altering the levels of hAPP (Fig. 6a), Aβ1-x (Fig. 6b), Aβ1−42 (Fig. 6c), or the Aβ1−42/Aβ1-x ratio (Fig. 6d). Removal or reduction of GIVA-PLA2 also did not alter Aβ deposition, astroglial activation (GFAP immunostaining), or microglial numbers (Iba-1 immunostaining) (data not shown). These findings suggest that GIVA-PLA2 reduction blocks or counteracts AD-related abnormalities downstream of Aβ production and deposition.

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