The function of sphingolipids in different pathogenesis of Alzheimer's disease: A comprehensive review
Open accessAbstract
Sphingolipids (SPLs) represent a highly diverse and structurally complex lipid class. The discussion of SPL metabolism-related issues is of importance in understanding the neuropathological progression of Alzheimer's disease (AD). AD is characterized by the accumulation of extracellular deposits of the amyloid β-peptide (Aβ) and intraneuronal aggregates of the microtubule-associated protein tau. Critical roles of Aβ oligomer deposited and ganglioside GM1 could be formed as "seed" from insoluble GAβ polymer in initiating the pathogenic process, while tau might also mediate SPLs and their toxicity. The interaction between ceramide and α-Synuclein (α-Syn) accelerates the aggregation of ferroptosis and exacerbates the pathogenesis of AD. For instance, reducing the levels of SPLs can mitigate α-Syn accumulation and inhibit AD progression. Meanwhile, loss of SPLs may inhibit the expression of APOE4 and confer protection against AD, while the loss of APOE4 expression also disrupts SPLs homeostasis. Moreover, the heightened activation of sphingomyelinase promotes the ferroptosis signaling pathway, leading to exacerbated AD symptoms. Ferroptosis plays a vital role in the pathological progression of AD by influencing Aβ, tau, APOE, and α-Syn. Conversely, the development of AD also exacerbates the manifestation of ferroptosis and SPLs. We are compiling the emerging techniques (Derivatization and IM-MS) of sphingolipidomics, to overcome the challenges of AD diagnosis and treatment. In th…
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Abnormal sphingolipid levels are linked to neuroinflammatory disorders.
“These abnormal changes in sphingolipid levels have been closely linked to neuroinflammatory disorders, as they play a crucial role in cell signaling and are, therefore, frequently discussed as potential therapeutic targets (45, 46).”
From Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer’s disease mouse model (2025) · cites this paper as [45]
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1 retracted
Tsigelny, I. F., Crews, L., Desplats, P., Shaked, G. M., Sharikov, Y., Mizuno, H., Spencer, B., Rockenstein, E., Trejo, M., Platoshyn, O., et al. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003135 · Cited by 281 · see citing works
RetractedAlzheimer Disease: An Update on Pathobiology and Treatment Strategies
Long, J. M., & Holtzman, D. M. (2019) · Cell · doi:10.1016/j.cell.2019.09.001 · Cited by 3,204 · see citing works
Nelson, P. T., Alafuzoff, I., Bigio, E. H., Bouras, C., Braak, H., Cairns, N. J., Castellani, R. J., Crain, B. J., Davies, P., Tredici, K. D., et al. (2012) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e31825018f7 · Cited by 2,050 · see citing works
Alzheimer Mechanisms and Therapeutic Strategies
Huang, Y., & Mucke, L. (2012) · Cell · doi:10.1016/j.cell.2012.02.040 · Cited by 1,758 · see citing works
Iwai, A., Masliah, E., Yoshimoto, M., Ge, N., Flanagan, L., Rohan de Silva, H. A., Kittel, A., & Saitoh, T. (1995) · Neuron · doi:10.1016/0896-6273(95)90302-x · Cited by 1,316 · see citing works
Apolipoprotein E controls cerebrovascular integrity via cyclophilin A
Bell, R. D., Winkler, E. A., Singh, I., Sagare, A. P., Deane, R., Wu, Z., Holtzman, D. M., Betsholtz, C., Armulik, A., Sallstrom, J., et al. (2012) · Nature · doi:10.1038/nature11087 · Cited by 1,293 · see citing works
Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance
Castellano, J. M., Kim, J., Stewart, F. R., Jiang, H., DeMattos, R. B., Patterson, B. W., Fagan, A. M., Morris, J. C., Mawuenyega, K. G., Cruchaga, C., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002156 · Cited by 1,227 · see citing works
ApoE Promotes the Proteolytic Degradation of Aβ
Jiang, Q., Lee, C. Y. D., Mandrekar, S., Wilkinson, B., Cramer, P., Zelcer, N., Mann, K., Lamb, B., Willson, T. M., Collins, J. L., et al. (2008) · Neuron · doi:10.1016/j.neuron.2008.04.010 · Cited by 876 · see citing works
apoE isoform–specific disruption of amyloid β peptide clearance from mouse brain
Deane, R., Sagare, A., Hamm, K., Parisi, M., Lane, S., Finn, M. B., Holtzman, D. M., & Zlokovic, B. V. (2008) · Journal of Clinical Investigation · doi:10.1172/jci36663 · Cited by 771 · see citing works
Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses
Bertram, L., & Tanzi, R. E. (2008) · Nature Reviews Neuroscience · doi:10.1038/nrn2494 · Cited by 747 · see citing works
Park, M. W., Cha, H. W., Kim, J., Kim, J. H., Yang, H., Yoon, S., Boonpraman, N., Yi, S. S., Yoo, I. D., & Moon, J.-S. (2021) · Redox Biology · doi:10.1016/j.redox.2021.101947 · Cited by 683 · see citing works
Trem2 restrains the enhancement of tau accumulation and neurodegeneration by β-amyloid pathology
Lee, S.-H., Meilandt, W. J., Xie, L., Gandham, V. D., Ngu, H., Barck, K. H., Rezzonico, M. G., Imperio, J., Lalehzadeh, G., Huntley, M. A., et al. (2021) · Neuron · doi:10.1016/j.neuron.2021.02.010 · Cited by 300 · see citing works
SRF and myocardin regulate LRP-mediated amyloid-β clearance in brain vascular cells
Bell, R. D., Deane, R., Chow, N., Long, X., Sagare, A., Singh, I., Streb, J. W., Guo, H., Rubio, A., Van Nostrand, W., et al. (2009) · Nature Cell Biology · doi:10.1038/ncb1819 · Cited by 261 · see citing works
Hong, S., Ostaszewski, B. L., Yang, T., O’Malley, T. T., Jin, M., Yanagisawa, K., Li, S., Bartels, T., & Selkoe, D. J. (2014) · Neuron · doi:10.1016/j.neuron.2014.02.027 · Cited by 213 · see citing works
Molecular Mechanisms and Genetics of Oxidative Stress in Alzheimer’s Disease
Cioffi, F., Adam, R. H. I., & Broersen, K. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190863 · Cited by 204 · see citing works
Iron loading is a prominent feature of activated microglia in Alzheimer’s disease patients
Kenkhuis, B., Somarakis, A., de Haan, L., Dzyubachyk, O., IJsselsteijn, M. E., de Miranda, N. F. C. C., Lelieveldt, B. P. F., Dijkstra, J., van Roon-Mom, W. M. C., Höllt, T., et al. (2021) · Acta Neuropathologica Communications · doi:10.1186/s40478-021-01126-5 · Cited by 184 · see citing works
He, X., Cooley, K., Chung, C. H. Y., Dashti, N., & Tang, J. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.3993-06.2007 · Cited by 107 · see citing works
CSF biomarker changes precede symptom onset of mild cognitive impairment
Moghekar, A., Li, S., Lu, Y., Li, M., Wang, M.-C., Albert, M., O’Brien, R., & For the BIOCARD Research Team (2013) · Neurology · doi:10.1212/01.wnl.0000435558.98447.17 · Cited by 103 · see citing works
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Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer’s disease mouse model
Wu, X., Miller, J. A., Lee, B. T. K., Wang, Y., & Ruedl, C. (2025) · Science Advances · doi:10.1126/sciadv.adq6038 · Cited by 67 · see citing works
“These abnormal changes in sphingolipid levels have been closely linked to neuroinflammatory disorders, as they play a crucial role in cell signaling and are, therefore, frequently discussed as potential therapeutic targets ( 45 , 46 ).”
- Authors
- Wang, X., Li, H., Sheng, Y., He, B., Liu, Z., Li, W., Yu, S., Wang, J., Zhang, Y., Chen, J., Qin, L., & Meng, X.
- Affiliations
- Zhejiang Chinese Medical University (CN)
- Fujian University of Traditional Chinese Medicine (CN)
- Corresponding author
- Chen, Jianyu
- Qin, Luping
- Meng, Xiongyu
- ORCID
- Venue
- Biomedicine & Pharmacotherapy
- Publisher
- Elsevier BV
- Published
- 2024-02
- Volume
- 171
- Pages
- 116071
- ISSN
- 0753-3322 (ISSN-L)
- OpenAlex
- W4390631060
- Cited by
- 29
- References
- 18
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 8
- FWCI
- 1.66
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Biomedicine & Pharmacotherapy (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Natural Science Foundation of Zhejiang Province (LGC20B050010, LQ22H270004)
- Zhejiang Chinese Medical University
- Medical Science and Technology Project of Zhejiang Province (2022490995)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- sphingolipids, Alzheimer's disease, amyloid-beta, tau protein, alpha-synuclein, ceramide, ferroptosis, APOE ε4, sphingomyelinase, sphingolipidomics, GM1 ganglioside, lipid metabolism, therapeutic target
- MeSH terms
- Alzheimer Disease, Ceramides, Humans, Sphingolipids, Amyloid beta-Peptides, tau Proteins, Apolipoprotein E4
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