. Phospholipase A2 reduction ameliorates cognitive deficits in a mouse model of Alzheimer's disease. Nat Neurosci. 2008 Nov;11(11):1311-8. PubMed.


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  1. The article by Sanchez-Mejia et al. (2008) in Nature Neuroscience reveals for the first time an important link between group IV phospholipase A2 (GIVA-PLA2) and cognitive deficits in the mouse model of Alzheimer’s disease. Using an unbiased lipidomics analysis protocol, this study demonstrated an increase in arachidonic acid (AA) and some of its metabolites in the brain tissues of transgenic mice expressing familial AD-mutant (hAPP) as compared with non-transgenic controls. The increase in AA was attributed to activation of GIVA-PLA2, a Ca2+-dependent enzyme with multiple phosphorylation sites (Sun et al., 2004). This phospholipase A2 prefers releasing AA and is stimulated by signaling cascades induced by G protein-coupled receptor agonists (Xu et al., 2002; Sun et al., 2004). The study by Sanchez-Mejia demonstrated the ability for oligomeric Aβ to stimulate phosphorylation of GIVA-PLA2 in mouse cortical neurons. This observation is similar to that reported by us earlier using rat cortical neurons (Shelat et al., 2008). However, while the study by Sanchez-Mejia et al. linked the increase in phospho-GIVA-PLA2 to activation of the AMPA receptor, Shelat et al. related Aβ activation to the NMDA receptor. Besides G protein-coupled receptors, oxidant compounds can also stimulate phospho-GIVA-PLA2 (Xu et al., 2003). In the study with rat cortical neurons, neuronal excitation by NMDA as well as by Aβ is linked to production of reactive oxygen species (ROS) by NADPH oxidase (Shelat et al., 2008). Consequently, these studies demonstrating a link between Aβ-mediated increase in ROS through NADPH oxidase and activation of GIVA-PLA2 provide important support for the oxidative hypothesis for AD and the observed increase in lipid peroxidation products during early phase of AD (Sun et al., 2007).

    Activation of GIVA-PLA2 not only produces AA for synthesis of a large number of eicosanoid metabolites, but AA is a known retrograde messenger and may directly modulate synaptic activity (see discussion in Shelat et al., 2008). Furthermore, GIVA-PLA2 activation produces lyso-phospholipids, compounds with detergent-like properties that may perturb membrane properties. There is also evidence that activation of GIVA-PLA2 can cause changes in neuronal membranes, including membrane physical properties (Hicks et al., 2008) and mitochondrial dysfunction (Zhu et al., 2006). In addition, increases in oxidative stress and MAPK pathways, signaling pathways associated with GIVA-PLA2, can alter changes in cytoskeleton properties and intercellular connections in astrocytes (Zhu et al., 2005). Based on these data, it is enticing to propose that in addition to targeting GIVA-PLA2, antioxidants may be included as potential therapy to ameliorate neurotoxicity of Aβ and progression of AD.

    A novelty in the study by Sanchez-Mejia et al. (2008) is the use of transgenic mice produced by crossing PLA2g4a-deficient mice with hAPP mice to provide data demonstrating that reduction of GIVA-PLA2 is associated with improved learning and memory. Indeed, this study together with other recent studies on GIVA-PLA2 provides strong support for the role of oxidative-membrane phospholipid degradation in neurodegenerative diseases and for future studies targeting NADPH oxidase and GIVA-PLA2 as potential therapeutics for treatment of these diseases in general and AD in particular.


    . Amyloid-beta peptide induces temporal membrane biphasic changes in astrocytes through cytosolic phospholipase A2. Biochim Biophys Acta. 2008 Nov;1778(11):2512-9. PubMed.

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    View all comments by Grace Sun
  2. Comment by Rene Sanchez-Mejia and Lennart Mucke
    We thank Tom Fagan, Tobias Hartmann, James Lee, and Grace Sun for their kind words about our paper. A few comments may help clarify some of the issues raised. The excellent work by Roberto Malinow (Hsieh et al., 2006) has identified mechanisms that may underlie the Aβ-dependent downregulation of AMPA receptors (AMPAR). However, to our knowledge, his work has not linked Aβ to an initial excitotoxic response or addressed the fact that, at the network level, Aβ elicits epileptiform activity (Palop et al., 2007). Our most recent study revealed for the first time that exposure of neurons to Aβ leads to an immediate increase in surface AMPAR levels. This increase in AMPAR was associated with an immediate increase in neuronal activity in response to Aβ and arachidonic acid (AA). These early Aβ-induced alterations may help explain the aberrant excitatory network activity observed in hAPP mice (Palop et al., 2007). In our culture model, the increase in AMPAR eventually subsided, and continued exposure to Aβ led to a decrease in surface AMPAR levels, consistent with the results previously reported by Roberto Malinow (Hsieh et al., 2006) and others (Shankar et al., 2007). As outlined in our paper, it is tempting to speculate that the delayed decrease in surface AMPAR levels may be triggered by the earlier increase in AMPAR and the resulting excitotoxicity.

    Our study also revealed that exposure of neurons to Aβ oligomers increases the activation/phosphorylation of GIVA PLA2 at relatively low concentrations of Aβ. Tobias Hartmann suggested that the decrease in phosphorylated GIVA PLA2 that we observed at higher concentrations of Aβ might be related to changes in the aggregation state of Aβ. Although we did exclude this possibility in our study by monitoring the aggregation state of Aβ oligomers after adding them to the culture medium, we would like to offer an alternate explanation. It is likely that at higher concentrations Aβ caused more profound cellular toxicity, resulting in impairments in the function of kinases that phosphorylate GIVA PLA2. These possibilities are not mutually exclusive.

    The comments by James Lee and Grace Sun further underline the potential significance of our work and provide important additional discussion points.


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    . Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci. 2007 Mar 14;27(11):2866-75. PubMed.

    View all comments by Lennart Mucke