CoChat
Sign Up
Cited by 244Sphingolipid Metabolism and SignalingAlzheimer's disease research and treatmentsLysosomal Storage Disorders Research

The DOI matches its Crossref record; 197 of the 199 references it cites were found in a registry or an index.

Ceramides in Alzheimer’s Disease: Key Mediators of Neuronal Apoptosis Induced by Oxidative Stress and A β Accumulation

Open access
Jazvinšćak Jembrek, Maja, Hof, Patrick R., Šimić, Goran·2015·Oxidative Medicine and Cellular Longevity
DOI 10.1155/2015/346783PMC PMC4458271
Open this paper in CoChat — free accountOpen PDF

Abstract

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.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1155/2015/346783

Cites

197 of 197 references verified0 citation errors · 0 not checkable

Statistics

Figures

Figure 1 Ceramide formation via de novo synthesis, recycling, and degradation. In the catabolic pathway, ceramides are generated through sphingomyelin hydrolysis by sphingomyelinases (SMases). In de novo synthesis, serine palmitoyltransferase (SPT) is the rate-limiting enzyme. In the recycling pathway, sphingosine, the product of sphingolipid catabolism, is salvaged through reacylation, resulting in ceramide production.
Figure 1 Ceramide formation via de novo synthesis, recycling, and degradation. In the catabolic pathway, ceramides are generated through sphingomyelin hydrolysis by sphingomyelinases (SMases). In de novo synthesis, serine palmitoyltransferase (SPT) is the rate-limiting enzyme. In the recycling pathway, sphingosine, the product of sphingolipid catabolism, is salvaged through reacylation, resulting in ceramide production.CC BY · PubMed Central
Figure 2 Role of ceramides in neuronal apoptosis. Overexpressed ceramides may provoke apoptosis by directly participating in ROS generation, through modulation of mitogen-activated protein kinases (MAPKs) signalling pathways, and by inhibition of prosurvival phosphatidylinositol 3-kinase (PI3-K)/Akt pathway via protein phosphatase 2A (PP2A) dephosphorylation, leading to activation of Bad and glycogen synthase 3β (GSK-3β). These cascades of biochemical alterations ultimately lead to neuronal death by diverse mechanisms, including depolarization and permeabilization of mitochondria (Δψ m), Bcl-2 depletion and Bax increase, cytochrome c release, and caspase-3 activation.
Figure 2 Role of ceramides in neuronal apoptosis. Overexpressed ceramides may provoke apoptosis by directly participating in ROS generation, through modulation of mitogen-activated protein kinases (MAPKs) signalling pathways, and by inhibition of prosurvival phosphatidylinositol 3-kinase (PI3-K)/Akt pathway via protein phosphatase 2A (PP2A) dephosphorylation, leading to activation of Bad and glycogen synthase 3β (GSK-3β). These cascades of biochemical alterations ultimately lead to neuronal death by diverse mechanisms, including depolarization and permeabilization of mitochondria (Δψ m), Bcl-2 depletion and Bax increase, cytochrome c release, and caspase-3 activation.CC BY · PubMed Central
Figure 3 Interplay between ceramides, Aβ and oxidative stress. Increased levels of ceramides directly increase levels of Aβ by increasing the half-life of BACE1 through posttranslational stabilization. As a positive feedback loop, the generated Aβ induces a further increase in ceramide levels by activating SMases activities in a ROS-dependent fashion. Aβ promotes accumulation of free radicals via NADPH oxidase activation and glutathione (GSH) depletion and induces membrane oxidative stress leading to generation of 4-hydroxynonenal (HNE), the neurotoxic product that exacerbates neuronal death through protein adduct formation, impairment of glucose metabolism, and ATP depletion.
Figure 3 Interplay between ceramides, Aβ and oxidative stress. Increased levels of ceramides directly increase levels of Aβ by increasing the half-life of BACE1 through posttranslational stabilization. As a positive feedback loop, the generated Aβ induces a further increase in ceramide levels by activating SMases activities in a ROS-dependent fashion. Aβ promotes accumulation of free radicals via NADPH oxidase activation and glutathione (GSH) depletion and induces membrane oxidative stress leading to generation of 4-hydroxynonenal (HNE), the neurotoxic product that exacerbates neuronal death through protein adduct formation, impairment of glucose metabolism, and ATP depletion.CC BY · PubMed Central
Figure 4 Interplay between neurons and astroglia in sphingolipid metabolism. Conditioned medium from palmitic acid- (PA-) treated astrocytes upregulates neuronal β-secretase (BACE1) leading to Aβ accumulation. PA increases de novo synthesis of ceramide and downregulates glucose uptake in astroglia. PA-induced activation of serine palmitoyltransferase (SPT) leads to production of proinflammatory cytokines, which after release in surrounding media activate neuronal sphingomyelinases (SMases), increase the ceramide pool, and ultimately lead to increase in Aβ accumulation.
Figure 4 Interplay between neurons and astroglia in sphingolipid metabolism. Conditioned medium from palmitic acid- (PA-) treated astrocytes upregulates neuronal β-secretase (BACE1) leading to Aβ accumulation. PA increases de novo synthesis of ceramide and downregulates glucose uptake in astroglia. PA-induced activation of serine palmitoyltransferase (SPT) leads to production of proinflammatory cytokines, which after release in surrounding media activate neuronal sphingomyelinases (SMases), increase the ceramide pool, and ultimately lead to increase in Aβ accumulation.CC BY · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

1 retracted

Show all 199 references

Research works printed but not linked: 8

  1. 1998, Periodicum Biologorum, 100, 165
  2. 10.1002/(sici)1096-9861(19970324)379:4lt;482::aid-cne2>3.0.co;2-z · DOI
  3. 2011, International Journal of Biochemistry and Molecular Biology, 2, 347
  4. 10.1016/j.freeradbiomed.2004.12.019 · DOI
  5. 2008, Collegium Antropologicum, 32, 51
  6. 2014, The Biochemical Journal, 465, 371
  7. 2009, Molecular Neurodegeneration, 4, article 47
  8. 10.1002/(sici)1097-4547(19971101)50:360;466::aid-jnr1362;3.0.co;2-4 · DOI

Cited by

Sorted by citations

See all 244

Related

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)
ORCID
Venue
Oxidative Medicine and Cellular Longevity
Publisher
Wiley
Published
2015
Volume
2015
Pages
1-17
ISSN
  • 1942-0994 (ISSN-L)
  • 1942-0900
DOI
10.1155/2015/346783
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
Licence
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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review