ArticleThe Journal of biological chemistry2012
Astrocytes secrete exosomes enriched with proapoptotic ceramide and prostate apoptosis response 4 (PAR-4): potential mechanism of apoptosis induction in Alzheimer disease (AD).
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 223 papers.
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Who cites it
223 citing papers in PubMed, 355 citations in OpenAlex.
- Treatment of animal models of Alzheimer's disease with extracellular vesicles or exosomes and involvement of microRNAs.Neural regeneration research · 2026Article
- A Novel Reporter Mouse for Astrocyte-Derived Extracellular Vesicles Reveals Enrichment of Cargo at Neuronal Mitochondria.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Neuroinflammation in Alzheimer's and Parkinson's diseases: pathogenic mechanisms and therapeutic strategies.Translational neurodegeneration · 2026Review
- The sperm survival switch: circRNA-mediated regulatory loops control apoptotic signalling in human spermatozoa.Cell death discovery · 2026Article
- Hydrophobic interaction chromatography resolves extracellular vesicle fractions with distinct lipidomic signatures.Scientific reports · 2026Article
- Extracellular Vesicles in Alzheimer's Disease: Mechanisms, Biomarkers, and Therapeutic Engineering.International journal of molecular sciences · 2026Review
- A novel reporter mouse for astrocyte-derived extracellular vesicles reveals trafficking of cargo to neuronal mitochondria.bioRxiv : the preprint server for biology · 2026Article
- Extracellular Vesicles in Alzheimer's Disease: Dual Roles in Pathogenesis, Promising Avenues for Diagnosis and Therapy.Pharmaceutics · 2026Review
- Vesicular Rps6 Released by Astrocytes in an Experimental Model of AD Regulates Local Translation and Enhances Synaptic Integrity in Neurones.Journal of extracellular vesicles · 2025Article
- Functional Specificity of Astrocyte Subtypes in Alzheimer's Disease: Decoding Disease Mechanisms Through Network-based Analysis of Integrated Single-Nuclei Multi-Omic Data.Molecular neurobiology · 2025Article
- Exosomal Non-Coding RNAs as Potential Biomarkers for Alzheimer's Disease: Advances and Perspectives in Translational Research.International journal of molecular sciences · 2025Review
- Small Extracellular Vesicles in Neurodegenerative Disease: Emerging Roles in Pathogenesis, Biomarker Discovery, and Therapy.International journal of molecular sciences · 2025Review
- Article
- Lipid metabolism, remodelling and intercellular transfer in the CNS.Nature reviews. Neuroscience · 2025Review
- Zipper-interacting protein kinase mediates neuronal cell death and cognitive dysfunction in traumatic brain injury via regulating DEDD.Cell death & disease · 2025Article
- Roles, Functions, and Pathological Implications of Exosomes in the Central Nervous System.International journal of molecular sciences · 2025Review
- The Role of Small Extracellular Vesicles Derived from Glial Cells in the Central Nervous System under both Normal and Pathological Conditions.Neurochemical research · 2025Review
- Extracellular Vesicles Derived from FGF2-Primed Astrocytes Against Mitochondrial and Synaptic Toxicities in Parkinson's Disease.International journal of nanomedicine · 2025Article
- Unravelling neuronal and glial differences in ceramide composition, synthesis, and sensitivity to toxicity.Communications biology · 2024Article
- Exosomes in Central Nervous System Diseases: A Comprehensive Review of Emerging Research and Clinical Frontiers.Biomolecules · 2024Review
163 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Amyloid protein is well known to induce neuronal cell death, whereas only little is known about its effect on astrocytes. We found that amyloid peptides activated caspase 3 and induced apoptosis in primary cultured astrocytes, which was prevented by caspase 3 inhibition. Apoptosis was also prevented by shRNA-mediated down-regulation of PAR-4, a protein sensitizing cells to the sphingolipid ceramide. Consistent with a potentially proapoptotic effect of PAR-4 and ceramide, astrocytes surrounding amyloid plaques in brain sections of the 5xFAD mouse (and Alzheimer disease patient brain) showed caspase 3 activation and were apoptotic when co-expressing PAR-4 and ceramide. Apoptosis was not observed in astrocytes with deficient neutral sphingomyelinase 2 (nSMase2), indicating that ceramide generated by nSMase2 is critical for amyloid-induced apoptosis. Antibodies against PAR-4 and ceramide prevented amyloid-induced apoptosis in vitro and in vivo, suggesting that apoptosis was mediated by exogenous PAR-4 and ceramide, potentially associated with secreted lipid vesicles. This was confirmed by the analysis of lipid vesicles from conditioned medium showing that amyloid peptide induced the secretion of PAR-4 and C18 ceramide-enriched exosomes. Exosomes were not secreted by nSMase2-deficient astrocytes, indicating that ceramide generated by nSMase2 is critical for exosome secretion. Consistent with the ceramide composition in amyloid-induced exosomes, exogenously added C18 ceramide restored PAR-4-containing exosome secretion in nSMase2-deficient astrocytes. Moreover, isolated PAR-4/ceramide-enriched exosomes were taken up by astrocytes and induced apoptosis in the absence of amyloid peptide. Taken together, we report a novel mechanism of apoptosis induction by PAR-4/ceramide-enriched exosomes, which may critically contribute to Alzheimer disease.
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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.