{"doi":"10.1016/j.ibneur.2023.02.005","title":"Neuroprotective properties of anti-apoptotic BCL-2 proteins in 5xFAD mouse model of Alzheimer’s disease","abstract":"Alzheimer's disease (AD) is the most common cause of dementia. An early feature of the AD pathology is the dysregulation of intracellular Ca2+ signaling in neurons. In particular, increased Ca2+ release from endoplasmic reticulum-located Ca2+ channels, including inositol-1,4,5-trisphosphate type 1 receptors (IP3R1) and ryanodine receptors type 2 (RyR2), have been extensively reported. Known for its anti-apoptotic properties, Bcl-2 also has the ability to bind to and inhibit the Ca2+-flux properties of IP3Rs and RyRs. In this study, the hypothesis that the expression of Bcl-2 proteins can normalize dysregulated Ca2+ signaling in a mouse model of AD (5xFAD) and thereby prevent or slow the progression of AD was examined. Therefore, stereotactic injections of adeno-associated viral vectors expressing Bcl-2 proteins were performed in the CA1 region of the 5xFAD mouse hippocampus. In order to assess the importance of the association with IP3R1, the Bcl-2K17D mutant was also included in these experiments. This K17D mutation has been previously shown to decrease the association of Bcl-2 with IP3R1, thereby impairing its ability to inhibit IP3R1 while not affecting Bcl-2′s ability to inhibit RyRs. Here, we demonstrate that Bcl-2 protein expression leads to synaptoprotective and amyloid-protective effects in the 5xFAD animal model. Several of these neuroprotective features are also observed by Bcl-2K17D protein expression, suggesting that these effects are not associated with Bcl-2-mediated inhibition of IP3R1. Potential mechanisms for this Bcl-2 synaptoprotective action may be related to its ability to inhibit RyR2 activity as Bcl-2 and Bcl-2K17D are equally potent in inhibiting RyR2-mediated Ca2+ fluxes. This work indicates that Bcl-2-based strategies hold neuroprotective potential in AD models, though the underlying mechanisms requires further investigation.","journal":"IBRO Neuroscience Reports","year":2023,"id":339355,"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":16,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9505,"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":641825,"name":"Manon Callens","orcid":"0000-0003-2847-8674","position":1,"is_corresponding":false},{"id":1072955,"name":"Marina Polozova","orcid":"0000-0001-6678-1688","position":2,"is_corresponding":false},{"id":1073356,"name":"A. Gordeev","orcid":null,"position":3,"is_corresponding":false},{"id":1072956,"name":"Margarita Chigriai","orcid":"0000-0002-5640-0404","position":4,"is_corresponding":false},{"id":1072957,"name":"Anastasiya Rakovskaya","orcid":"0000-0002-9709-9769","position":5,"is_corresponding":false},{"id":1072958,"name":"Anastasiia Ilina","orcid":"0000-0002-7112-1534","position":6,"is_corresponding":false},{"id":254986,"name":"Ekaterina Pchitskaya","orcid":"0000-0002-3644-6886","position":7,"is_corresponding":false},{"id":232820,"name":"Chris Van den Haute","orcid":"0000-0002-6650-3845","position":8,"is_corresponding":false},{"id":638894,"name":"Tim Vervliet","orcid":"0000-0002-4030-5875","position":9,"is_corresponding":false},{"id":301151,"name":"Geert Bultynck","orcid":"0000-0002-5968-4828","position":10,"is_corresponding":false},{"id":254987,"name":"Ilya Bezprozvanny","orcid":"0000-0001-7006-6951","position":11,"is_corresponding":false},{"id":471742,"name":"Daria Chernyuk","orcid":"0000-0001-5542-372X","position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":null,"created_at":"2026-07-19T01:10:45.048445Z","pmid":"36926591","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":[]}