ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2010
Phospholipase d2 ablation ameliorates Alzheimer's disease-linked synaptic dysfunction and cognitive deficits.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 95 papers.
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Who cites it
95 citing papers in PubMed, 175 citations in OpenAlex.
- Phosphatidic Acid-TRIM59-Olig2 Signaling Couples Metabolic Dysfunction to Myelination Failure in PWMI.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Spatial-temporal lipidomics reveals dysregulated lipid metabolism in mouse brain during Alzheimer's disease progression.Journal of advanced research · 2026Article
- Circulating lipids uncover early membrane disruption as a primary event preceding Alzheimer's disease onset.Research square · 2026Article
- Exploring the PLD1-tau interaction in Frontotemporal Dementia.bioRxiv : the preprint server for biology · 2026Article
- Plasma Phospholipid Biomarkers Related to the Risk of Cognitive Decline in the Elderly: Results from a Cohort Study.Nutrients · 2026Article
- Designing New Natural-Mimetic Phosphatidic Acid: A Versatile and Innovative Synthetic Strategy for Glycerophospholipid Research.Angewandte Chemie (International ed. in English) · 2025Article
- cAMP/PKA signaling regulates TDP-43 aggregation and mislocalization.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Phospholipase Modulation of Synaptic Membrane Landscape: Driving Force Behind Memory Formation?Cold Spring Harbor perspectives in biology · 2024Review
- Phospholipase D, a Novel Therapeutic Target Contributes to the Pathogenesis of Neurodegenerative and Neuroimmune Diseases.Analytical cellular pathology (Amsterdam) · 2024Review
- Therapeutic Strategies Aimed at Improving Neuroplasticity in Alzheimer Disease.Pharmaceutics · 2023Review
- Cholesterol Regulation of Membrane Proteins Revealed by Two-Color Super-Resolution Imaging.Membranes · 2023Review
- Discovery of Phospholipase D Inhibitors with Improved Drug-like Properties and Central Nervous System Penetrance.ACS medicinal chemistry letters · 2022Article
- Effects of APOE4 allelic dosage on lipidomic signatures in the entorhinal cortex of aged mice.Translational psychiatry · 2022Article
- Targeting PLD2 in adipocytes augments adaptive thermogenesis by improving mitochondrial quality and quantity in mice.The Journal of experimental medicine · 2022Article
- PLD1 promotes reactive oxygen species production in vascular smooth muscle cells and injury-induced neointima formation.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2022Article
- Membrane lipid raft homeostasis is directly linked to neurodegeneration.Essays in biochemistry · 2021Review
- Key Disease Mechanisms Linked to Alzheimer's Disease in the Entorhinal Cortex.International journal of molecular sciences · 2021Article
- Ras GEF Mouse Models for the Analysis of Ras Biology and Signaling.Methods in molecular biology (Clifton, N.J.) · 2021Article
- D-series Resolvins activate Phospholipase D in phagocytes during inflammation and resolution.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2020Article
- Phospholipase D1 and D2 Synergistically Regulate Thrombus Formation.International journal of molecular sciences · 2020Article
35 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
13 authors at 2 institutions in 2 countries.
Funding
Abstract
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. 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.