ArticlePLoS genetics2021
PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer's disease.
Article in PLoS genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 58 citations in OpenAlex.
- Experimental model of ventilator-induced lung injury induces proteomic signatures of neurodegeneration in the hippocampus.Intensive care medicine experimental · 2026Article
- Targeting PLD3 Reverses the Immunosuppressive Niche by Reprogramming Tumor-Associated Macrophages and Potentiates Antitumor Immunity.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- PLD3-mediated Mitophagy Attenuates Neuronal Ferroptosis and Promotes Functional Recovery after Spinal Cord Injury.Molecular neurobiology · 2026Article
- Preclinical serum alterations and tissue changes in protein and gene expression of early cerebrospinal fluid-validated biomarkers in scrapie.Veterinary research · 2026Article
- Benchmarking Lysosome Enrichment Methods: A Guide for Research and Clinical Translation.Analytical chemistry · 2026Article
- Phospholipase D: emerging therapeutic targets in signaling, metabolism, and immune-oncology.Cell communication and signaling : CCS · 2025Review
- Macrophage Phospholipase D3 promotes atherosclerosis via exacerbating foam cell formation and inducing inflammatory responses.International journal of cardiology. Heart & vasculature · 2025Article
- Exosome-Mediated Delivery of a PLD1 Modulator Overcomes Bioavailability Hurdles to Target Synaptopathy in Neurodegenerative Diseases.Pharmaceutical research · 2025Article
- IQGAP2 regulates blood-brain barrier immune dynamics.iScience · 2025Article
- Multi-Omics Analysis of Hippocampus in Rats Administered Trimethyltin Chloride.Neurotoxicity research · 2025Article
- Inhibition of amyloid beta oligomer accumulation by NU-9: A unifying mechanism for the treatment of neurodegenerative diseases.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Subcellular proteomics and iPSC modeling uncover reversible mechanisms of axonal pathology in Alzheimer's disease.Nature aging · 2025Article
- Autophagy in alzheimer disease pathogenesis and its therapeutic values.Autophagy reports · 2025Review
- Crystal structure of Alzheimer's disease phospholipase D3 provides a molecular basis for understanding its normal and pathological functions.The FEBS journal · 2024Article
- PLD3 and PLD4 synthesize S,S-BMP, a key phospholipid enabling lipid degradation in lysosomes.Cell · 2024Article
- Article
- The V-ATPase complex component RNAseK is required for lysosomal hydrolase delivery and autophagosome degradation.Nature communications · 2024Article
- Disruptions in axonal lysosome transport and its contribution to neurological disease.Current opinion in cell biology · 2024Review
- Comprehensive Overview of Alzheimer's Disease: Etiological Insights and Degradation Strategies.International journal of molecular sciences · 2024Review
- The necroptosis cell death pathway drives neurodegeneration in Alzheimer's disease.Acta neuropathologica · 2024Review
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Authors and funding
13 authors at 4 institutions in 1 country.
Funding
Abstract
Phospholipase D3 (PLD3) is a protein of unclear function that structurally resembles other members of the phospholipase D superfamily. A coding variant in this gene confers increased risk for the development of Alzheimer's disease (AD), although the magnitude of this effect has been controversial. Because of the potential significance of this obscure protein, we undertook a study to observe its distribution in normal human brain and AD-affected brain, determine whether PLD3 is relevant to memory and cognition in sporadic AD, and to evaluate its molecular function. In human neuropathological samples, PLD3 was primarily found within neurons and colocalized with lysosome markers (LAMP2, progranulin, and cathepsins D and B). This colocalization was also present in AD brain with prominent enrichment on lysosomal accumulations within dystrophic neurites surrounding β-amyloid plaques. This pattern of protein distribution was conserved in mouse brain in wild type and the 5xFAD mouse model of cerebral β-amyloidosis. We discovered PLD3 has phospholipase D activity in lysosomes. A coding variant in PLD3 reported to confer AD risk significantly reduced enzymatic activity compared to wild-type PLD3. PLD3 mRNA levels in the human pre-frontal cortex inversely correlated with β-amyloid pathology severity and rate of cognitive decline in 531 participants enrolled in the Religious Orders Study and Rush Memory and Aging Project. PLD3 levels across genetically diverse BXD mouse strains and strains crossed with 5xFAD mice correlated strongly with learning and memory performance in a fear conditioning task. In summary, this study identified a new functional mammalian phospholipase D isoform which is lysosomal and closely associated with both β-amyloid pathology and cognition.
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