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Ceramides in Alzheimer’s Disease: Key Mediators of Neuronal Apoptosis Induced by Oxidative Stress and A β Accumulation
Open accessAbstract
Alzheimer’s disease (AD), the most common chronic and progressive neurodegenerative disorder, is characterized by extracellular deposits of amyloid β -peptides (A β ) and intracellular deposits of hyperphosphorylated tau (phospho-tau) protein. Ceramides, the major molecules of sphingolipid metabolism and lipid second messengers, have been associated with AD progression and pathology via A β generation. Enhanced levels of ceramides directly increase A β through stabilization of β -secretase, the key enzyme in the amyloidogenic processing of A β precursor protein (APP). As a positive feedback loop, the generated oligomeric and fibrillar A β induces a further increase in ceramide levels by activating sphingomyelinases that catalyze the catabolic breakdown of sphingomyelin to ceramide. Evidence also supports important role of ceramides in neuronal apoptosis. Ceramides may initiate a cascade of biochemical alterations, which ultimately leads to neuronal death by diverse mechanisms, including depolarization and permeabilization of mitochondria, increased production of reactive oxygen species (ROS), cytochrome c release, Bcl-2 depletion, and caspase-3 activation, mainly by modulating intracellular signalling, particularly along the pathways related to Akt/PKB kinase and mitogen-activated protein kinases (MAPKs). This review summarizes recent findings related to the role of ceramides in oxidative stress-driven neuronal apoptosis and interplay with A β in the cascade of events ending in neuronal degeneration.
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“Elevated Cer levels have been associated with AD pathology, including promoting Aβ accumulation, mitochondrial dysfunction, and inflammation. 24 , 25”
From Protective mechanisms against Alzheimer's disease in APOE3‐Christchurch homozygous astrocytes (2025) · cites this paper as [25]
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“Ceramides are also known to initiate some of the pathological changes that drive AD progression. 24 , 25”
From Protective mechanisms against Alzheimer's disease in APOE3‐Christchurch homozygous astrocytes (2025) · cites this paper as [25]
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Metadata
- Authors
- Jazvinšćak Jembrek, M., Hof, P. R., & Šimić, G.
- Affiliations
- Laboratory for Molecular Neuropharmacology, Division of Molecular Medicine, Rudjer Bošković Institute, 10000 Zagreb, Croatia
- Icahn School of Medicine at Mount Sinai (US)
- University of Zagreb (HR)
- Venue
- Oxidative Medicine and Cellular Longevity
- Publisher
- Wiley
- Published
- 2015
- Volume
- 2015
- Pages
- 1-17
- ISSN
- 1942-0994 (ISSN-L)
- 1942-0900
- PMC
- PMC4458271
- OpenAlex
- W1484835368
- Cited by
- 244
- References
- 199
- Citations by year
- 2026: 13 · 2025: 22 · 2024: 26 · 2023: 23 · 2022: 27 · 2021: 29 · 2020: 21 · 2019: 29 · 2018: 20 · 2017: 21 · 2016: 10 · 2015: 3
- FWCI
- 1.74
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Oxidative Medicine and Cellular Longevity (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Repository of the Medical Faculty of the University of Zagreb (University of Zagreb) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Institutional Repository of the Ruđer Bošković Institute (Ruđer Bošković Institute) (submittedVersion, cc-by)
- Institutional Repository of the Ruđer Bošković Institute (Ruđer Bošković Institute) (submittedVersion, other-oa)
- Funders
- Croatian Ministry of Science, Education and Sport (098-0000000-2448, 09/16, AG005138)
- Croatian Science Foundation (098-0000000-2448, 09/16, AG005138)
- National Institutes of Health (098-0000000-2448, 09/16, AG005138)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
- Keywords
- ceramide, Alzheimer's disease, amyloid-beta, oxidative stress, neuronal apoptosis, sphingolipid metabolism, beta-secretase, sphingomyelinase, tau hyperphosphorylation, mitochondrial membrane permeabilization, reactive oxygen species, caspase-3, Akt signaling, MAPK signaling, neurodegeneration
- MeSH terms
- Alzheimer Disease, Animals, Ceramides, Humans, Neurons, Amyloid beta-Peptides, Apoptosis, Oxidative Stress
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