{"doi":"10.1002/alz.13058","title":"Low glucose induced Alzheimer's disease‐like biochemical changes in human induced pluripotent stem cell‐derived neurons is due to dysregulated O‐GlcNAcylation","abstract":"INTRODUCTION: Sporadic Alzheimer's disease (sAD) is the leading type of dementia. Brain glucose hypometabolism, along with decreased O-GlcNAcylation levels, occurs before the onset of symptoms and correlates with pathogenesis. Heretofore, the mechanisms involved and the roles of O-GlcNAcylation in sAD pathology largely remain unknown due to a lack of human models of sAD. METHODS: Human cortical neurons were generated from pluripotent stem cells (PSCs) and treated with glucose reduction media. RESULTS: We found a narrow window of glucose concentration that induces sAD-like phenotypes in PSC-derived neurons. With our model, we reveal that dysregulated O-GlcNAc, in part through mitochondrial dysfunction, causes the onset of sAD-like changes. We demonstrate the therapeutic potential of inhibiting O-GlcNAcase in alleviating AD-like biochemical changes. DISCUSSION: Our results suggest that dysregulated O-GlcNAc might be a direct molecular link between hypometabolism and sAD-like alternations. Moreover, this model can be exploited to explore molecular processes and for drug development. HIGHLIGHTS: Lowering glucose to a critical level causes AD-like changes in cortical neurons. Defective neuronal structure and function were also recapitulated in current model. Dysregulated O-GlcNAcylation links impaired glucose metabolism to AD-like changes. Mitochondrial abnormalities correlate with O-GlcNAcylation and precede AD-like phenotype. Our model provides a platform to study sAD as a metabolic disease in human neurons.","journal":"Alzheimer s & Dementia","year":2023,"id":333783,"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":22,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9568,"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":1062183,"name":"Nicholas C. Rust","orcid":null,"position":1,"is_corresponding":false},{"id":877572,"name":"Hsueh‐Fu Wu","orcid":"0000-0001-7892-7154","position":2,"is_corresponding":false},{"id":293356,"name":"Amelia Yin","orcid":null,"position":3,"is_corresponding":false},{"id":291181,"name":"Nadja Zeltner","orcid":"0000-0002-2978-2507","position":4,"is_corresponding":false},{"id":291085,"name":"Hang Yin","orcid":"0000-0002-9621-0138","position":5,"is_corresponding":false},{"id":299280,"name":"Gerald W. Hart","orcid":"0000-0001-7812-4351","position":6,"is_corresponding":false},{"id":522518,"name":"Chia‐Wei Huang","orcid":null,"position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":null,"created_at":"2026-07-19T01:09:44.297718Z","pmid":"37037474","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":[]}