{"doi":"10.1016/j.celrep.2020.108420","title":"Endosomal Dysfunction Induced by Directly Overactivating Rab5 Recapitulates Prodromal and Neurodegenerative Features of Alzheimer’s Disease","abstract":"Neuronal endosomal dysfunction, the earliest known pathobiology specific to Alzheimer's disease (AD), is mediated by the aberrant activation of Rab5 triggered by APP-β secretase cleaved C-terminal fragment (APP-βCTF). To distinguish pathophysiological consequences specific to overactivated Rab5 itself, we activate Rab5 independently from APP-βCTF in the PA-Rab5 mouse model. We report that Rab5 overactivation alone recapitulates diverse prodromal and degenerative features of AD. Modest neuron-specific transgenic Rab5 expression inducing hyperactivation of Rab5 comparable to that in AD brain reproduces AD-related Rab5-endosomal enlargement and mistrafficking, hippocampal synaptic plasticity deficits via accelerated AMPAR endocytosis and dendritic spine loss, and tau hyperphosphorylation via activated glycogen synthase kinase-3β. Importantly, Rab5-mediated endosomal dysfunction induces progressive cholinergic neurodegeneration and impairs hippocampal-dependent memory. Aberrant neuronal Rab5-endosome signaling, therefore, drives a pathogenic cascade distinct from β-amyloid-related neurotoxicity, which includes prodromal and neurodegenerative features of AD, and suggests Rab5 overactivation as a potential therapeutic target.","journal":"Cell Reports","year":2020,"id":52639,"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":130,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9531,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":266911,"name":"Seonil Kim","orcid":"0000-0002-0451-2180","position":1,"is_corresponding":false},{"id":266912,"name":"Shivakumar Subbanna","orcid":"0000-0001-6291-579X","position":2,"is_corresponding":false},{"id":269204,"name":"Cynthia Bleiwas","orcid":null,"position":3,"is_corresponding":false},{"id":266913,"name":"Chris N. Goulbourne","orcid":"0000-0003-1185-2682","position":4,"is_corresponding":false},{"id":266914,"name":"Philip Stavrides","orcid":"0000-0003-1225-3577","position":5,"is_corresponding":false},{"id":266915,"name":"Ying Jiang","orcid":"0000-0003-2432-8011","position":6,"is_corresponding":false},{"id":266916,"name":"Ju‐Hyun Lee","orcid":"0000-0002-0280-8375","position":7,"is_corresponding":false},{"id":266917,"name":"Sandipkumar Darji","orcid":"0000-0003-4197-4971","position":8,"is_corresponding":false},{"id":266918,"name":"Monika Pawlik","orcid":"0000-0003-0138-7529","position":9,"is_corresponding":false},{"id":269205,"name":"Chunfeng Huo","orcid":null,"position":10,"is_corresponding":false},{"id":269206,"name":"James Peddy","orcid":null,"position":11,"is_corresponding":false},{"id":266919,"name":"Martin J. Berg","orcid":"0000-0002-7353-8851","position":12,"is_corresponding":false},{"id":266920,"name":"John F. Smiley","orcid":"0000-0003-3739-7606","position":13,"is_corresponding":false},{"id":266921,"name":"Balapal S. Basavarajappa","orcid":"0000-0002-4429-8078","position":14,"is_corresponding":false},{"id":257655,"name":"Ralph A. Nixon","orcid":"0000-0001-5124-1021","position":15,"is_corresponding":false},{"id":266910,"name":"Anna Pensalfini","orcid":"0009-0006-7423-9147","position":0,"is_corresponding":true}],"reference_count":119,"raw_metadata":null,"created_at":"2026-07-18T20:43:25.742124Z","pmid":"33238112","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":[]}