Publicação
The role of phospholipase D2 in Alzheimer's disease
| Resumo: | Growing evidence implicates aberrant lipid signaling in Alzheimer‟s disease (AD). While phospholipases A2 and C have been recently shown to mediate key actions of amyloid β-peptide (Aβ) through a dysregulation of arachidonic acid and phosphatidylinositol-4,5-bisphosphate metabolism, respectively, the role of phospholipase D (PLD) has so far remained elusive. PLD produces phosphatidic acid (PA), a bioactive lipid involved in multiple aspects of cell physiology, including signaling and membrane trafficking processes. Here we show that oligomeric Aβ enhances PLD activity in cultured neurons and that this stimulatory effect does not occur upon ablation of PLD2 via gene targeting. Aβ fails to suppress long-term potentiation in PLD2-deficient hippocampal slices, suggesting that PLD2 is required for the synaptotoxic action of this peptide. In vivo PLD activity, as assessed by detection of phosphatidylethanol levels using mass spectrometry (MS) following ethanol injection, is also increased in the brain of a transgenic mouse model of AD (SwAPP). Furthermore, Pld2 ablation rescues memory deficits and confers synaptic protection in SwAPP mice despite a significant Aβ load. MS-based lipid analysis of Pld2 mutant brains in the presence or absence of the SwAPP transgene unmasks striking crosstalks between different PA species. This lipid analysis shows an exquisite acyl chain specificity and plasticity in the perturbation of PA metabolism, with the notable elevation in SwAPP brains of a pool of PA previously linked to degeneration. Collectively, our results point to specific molecular species of PA as key modulators of AD pathogenesis and identify PLD2 as a novel potential target for therapeutics. Moreover we expanded our MS analysis of the Pld2/SwAPP mice to other lipid groups, other than PA. We found that overexpression of the SwAPP transgene leads to significant increase in the ganglioside, GM3. Remarkably, Pld2 ablation leads to a decrease in GM3 in the non-transgenic background and to a rescue to normals in the SwAPP background. This lipidomic analysis uncovered interesting lipid signaling crosstalks that are modulated by PLD2 in the context of AD models. |
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| Autores principais: | Oliveira, Tiago Gil |
| Ano: | 2010 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade do Minho |
| Idioma: | inglês |
| Origem: | RepositóriUM - Universidade do Minho |
| Resumo: | Growing evidence implicates aberrant lipid signaling in Alzheimer‟s disease (AD). While phospholipases A2 and C have been recently shown to mediate key actions of amyloid β-peptide (Aβ) through a dysregulation of arachidonic acid and phosphatidylinositol-4,5-bisphosphate metabolism, respectively, the role of phospholipase D (PLD) has so far remained elusive. PLD produces phosphatidic acid (PA), a bioactive lipid involved in multiple aspects of cell physiology, including signaling and membrane trafficking processes. Here we show that oligomeric Aβ enhances PLD activity in cultured neurons and that this stimulatory effect does not occur upon ablation of PLD2 via gene targeting. Aβ fails to suppress long-term potentiation in PLD2-deficient hippocampal slices, suggesting that PLD2 is required for the synaptotoxic action of this peptide. In vivo PLD activity, as assessed by detection of phosphatidylethanol levels using mass spectrometry (MS) following ethanol injection, is also increased in the brain of a transgenic mouse model of AD (SwAPP). Furthermore, Pld2 ablation rescues memory deficits and confers synaptic protection in SwAPP mice despite a significant Aβ load. MS-based lipid analysis of Pld2 mutant brains in the presence or absence of the SwAPP transgene unmasks striking crosstalks between different PA species. This lipid analysis shows an exquisite acyl chain specificity and plasticity in the perturbation of PA metabolism, with the notable elevation in SwAPP brains of a pool of PA previously linked to degeneration. Collectively, our results point to specific molecular species of PA as key modulators of AD pathogenesis and identify PLD2 as a novel potential target for therapeutics. Moreover we expanded our MS analysis of the Pld2/SwAPP mice to other lipid groups, other than PA. We found that overexpression of the SwAPP transgene leads to significant increase in the ganglioside, GM3. Remarkably, Pld2 ablation leads to a decrease in GM3 in the non-transgenic background and to a rescue to normals in the SwAPP background. This lipidomic analysis uncovered interesting lipid signaling crosstalks that are modulated by PLD2 in the context of AD models. |
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