{"doi":"10.1002/ctd2.236","title":"The impact of sulfatide loss on the progress of Alzheimer's disease","abstract":"Alzheimer's disease (AD) is a progressive neurogenerative disorder associated with age, marked by a gradual decline in memory, cognitive impairment, and behavioural changes. Among its key pathological traits is the presence of extracellular neuritic plaques enriched in β-amyloid coupled with a decline in neuronal synapses and an accumulation of lipid granules. Within the brain, myelinating glial cells play a crucial role in providing electrical insulation and facilitating the swift propagation of action potential along neuronal axons. Approximately 80% of myelin's dry weight is composed of lipids,1 which not only establish an optimal membrane fluidity but also provide the essential hydrophobic insulation required for effective action potential conduction. The composition of myelin lipids includes cholesterol, phospholipids, and sphingolipids. Among sphingolipids, sphingomyelin, ceramides, and sulfatide (ST) stand out as prominent enriched constituents within myelin membranes.1 ST, predominantly located at the outer leaflet of the cell membrane across all eukaryotic cells, is associated with a variety of cellular processes including platelet aggregation, cell survival, immune responses, and host–pathogen interactions.2 The enzyme cerebroside sulfotransferase, located within the Golgi apparatus, catalyses the conversion of galactocerebroside into ST, whereas the turnover of ST is mediated by the lysosomal arylsulfatase/saposin B complex.2 Lipidomic and metabolomic studies reveal disrupted lipid metabolism in early stages of individuals with AD, evidenced by reduced ST levels (e.g., the study of Hong et al.3) and by near-total depletion of the sphingolipid in the brains of deceased individuals with AD.4 Accumulating evidence underscores the role of glia-mediated inflammation as a major contributor to the progression of AD, including cognitive shortfalls.5 In mice where the enzyme cerebroside sulfotransferase is conditionally knocked out, the loss of ST in the central nervous system triggers the activation of microglia and astrocytes associated with AD, the upregulation of AD-related genes, and the modulation of the immune/microglia network, all of which promote cognitive deficits and neuroinflammation.6 Another major player that is impacted by ST deficiency is apolipoprotein E (ApoE), which participates in the transport of ST to brain cells.7 ST-loaded ApoE is recognised by members of the low-density lipoprotein receptor superfamily, leading to most ST molecules undergoing degradation within late endosomal and lysosomal compartments. The deposition of β-amyloid, resulting from the breakdown of the amyloid protein precursor, serves as a hallmark of AD. The association of ApoE to ST facilitates β-amyloid clearance via an endocytic pathway.8 Experiments carried out using a knockout mice model with deficient levels of ST have revealed that the expression of the ApoE gene is upregulated as a compensatory response to the loss of ST; however, the increased ApoE levels do not trigger the activation of astrocytes and microglia.6 The spinal cord serves as a bridge between the central nervous system and the rest of the body. Clinical dysfunction of the spinal cord has shown associations with patients affected by AD. The degeneration of the spinal cord has been proposed as an internal marker for AD-related dementia.9 Moreover, spinal cord injury has been identified as a factor that increases susceptibility to the development of AD.10 In a recent publication by Xianlin Han and his team, new insights into the impact of ST loss on the progression of AD have emerged. Using shotgun lipidomics, the authors have pinpointed a decrease in the overall lipid content within the spinal cords of AD individuals when compared to the lipid composition observed in the spinal cords of those with normal cognitive function.11 The impact of these changes was more pronounced in white matter compared to grey matter. The reduction in ST levels within myelin lipids e","journal":"Clinical and Translational Discovery","year":2023,"id":378908,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9571,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":940885,"name":"Daniel G. S. Capelluto","orcid":"0000-0002-0412-4508","position":1,"is_corresponding":false},{"id":628658,"name":"Carla V. Finkielstein","orcid":"0000-0002-8417-4643","position":0,"is_corresponding":true}],"reference_count":11,"raw_metadata":null,"created_at":"2026-07-19T01:16:48.594070Z","pmid":"38463462","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}