{"doi":"10.3233/jad-231169","title":"Sildenafil Reverses the Neuropathological Alzheimer’s Disease Phenotype in Cholinergic-Like Neurons Carrying the Presenilin 1 E280A Mutation","abstract":"<jats:p>Background: Familial Alzheimer’s disease (FAD) presenilin 1 E280A (PSEN 1 E280A) is characterized by functional impairment and the death of cholinergic neurons as a consequence of amyloid-β (Aβ) accumulation and abnormal phosphorylation of the tau protein. Currently, there are no available therapies that can cure FAD. Therefore, new therapies are urgently needed for treating this disease. Objective: To assess the effect of sildenafil (SIL) on cholinergic-like neurons (ChLNs) harboring the PSEN 1 E280A mutation. Methods: Wild-type (WT) and PSEN 1 E280A ChLNs were cultured in the presence of SIL (25μM) for 24 h. Afterward, proteinopathy, cell signaling, and apoptosis markers were evaluated via flow cytometry and fluorescence microscopy. Results: We found that SIL was innocuous toward WT PSEN 1 ChLNs but reduced the accumulation of intracellular Aβ fragments by 87%, decreased the non-physiological phosphorylation of the protein tau at residue Ser202/Thr205 by 35%, reduced the phosphorylation of the proapoptotic transcription factor c-JUN at residue Ser63/Ser73 by 63%, decreased oxidized DJ-1 at Cys106-SO3 by 32%, and downregulated transcription factor TP53 (tumor protein p53), BH-3-only protein PUMA (p53 upregulated modulator of apoptosis), and cleaved caspase 3 (CC3) expression by 20%, 32%, and 22%, respectively, compared with untreated mutant ChLNs. Interestingly, SIL also ameliorated the dysregulation of acetylcholine-induced calcium ion (Ca2+) influx in PSEN 1 E280A ChLNs. Conclusions: Although SIL showed no antioxidant capacity in the oxygen radical absorbance capacity and ferric ion reducing antioxidant power assays, it might function as an anti-amyloid and antiapoptotic agent and functional neuronal enhancer in PSEN 1 E280A ChLNs. Therefore, the SIL has therapeutic potential for treating FAD.</jats:p>","journal":"Journal of Alzheimer's Disease","year":2024,"id":595818,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":563692,"name":"Marlene Jiménez-Del-Río","orcid":"0000-0003-3477-2386","position":1,"is_corresponding":false},{"id":563691,"name":"Carlos Velez‐Pardo","orcid":"0000-0002-0557-0411","position":2,"is_corresponding":false},{"id":1525884,"name":"Daniela Giraldo-Berrio","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Sildenafil Reverses the Neuropathological Alzheimer’s Disease Phenotype in Cholinergic-Like Neurons Carrying the Presenilin 1 E280A Mutation","abstract":"<jats:p>Background: Familial Alzheimer’s disease (FAD) presenilin 1 E280A (PSEN 1 E280A) is characterized by functional impairment and the death of cholinergic neurons as a consequence of amyloid-β (Aβ) accumulation and abnormal phosphorylation of the tau protein. Currently, there are no available therapies that can cure FAD. Therefore, new therapies are urgently needed for treating this disease. Objective: To assess the effect of sildenafil (SIL) on cholinergic-like neurons (ChLNs) harboring the PSEN 1 E280A mutation. Methods: Wild-type (WT) and PSEN 1 E280A ChLNs were cultured in the presence of SIL (25μM) for 24 h. Afterward, proteinopathy, cell signaling, and apoptosis markers were evaluated via flow cytometry and fluorescence microscopy. Results: We found that SIL was innocuous toward WT PSEN 1 ChLNs but reduced the accumulation of intracellular Aβ fragments by 87%, decreased the non-physiological phosphorylation of the protein tau at residue Ser202/Thr205 by 35%, reduced the phosphorylation of the proapoptotic transcription factor c-JUN at residue Ser63/Ser73 by 63%, decreased oxidized DJ-1 at Cys106-SO3 by 32%, and downregulated transcription factor TP53 (tumor protein p53), BH-3-only protein PUMA (p53 upregulated modulator of apoptosis), and cleaved caspase 3 (CC3) expression by 20%, 32%, and 22%, respectively, compared with untreated mutant ChLNs. Interestingly, SIL also ameliorated the dysregulation of acetylcholine-induced calcium ion (Ca2+) influx in PSEN 1 E280A ChLNs. Conclusions: Although SIL showed no antioxidant capacity in the oxygen radical absorbance capacity and ferric ion reducing antioxidant power assays, it might function as an anti-amyloid and antiapoptotic agent and functional neuronal enhancer in PSEN 1 E280A ChLNs. Therefore, the SIL has therapeutic potential for treating FAD.</jats:p>","is_dataset_classified":null,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"38728184","pmcid":null,"openalex_id":"https://openalex.org/W4396792920","authors":[],"funders":[],"total_grants":0,"fwci":0.5598,"citation_percentile":0.64423675,"influential_citations":0,"citation_trend":[{"year":2025,"count":2},{"year":2026,"count":1}],"oa_status":"closed","license":null,"oa_locations":[{"url":"https://content.iospress.com/download?id=10.3233/JAD-231169","host_type":"publisher"},{"url":"https://doi.org/10.3233/jad-231169","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/38728184","host_type":"repository"}],"fields_of_study":["Phosphodiesterase function and regulation","Nicotinic Acetylcholine Receptors Study","Cancer, Stress, Anesthesia, and Immune Response"],"mesh_terms":["Sildenafil Citrate","Alzheimer Disease","Animals","Cells, Cultured","Humans","Mutation","Phenotype","Phosphorylation","Amyloid beta-Peptides","tau Proteins","Mice","Presenilin-1","Cholinergic Neurons"],"keywords":["Presenilin","Cholinergic","Phenotype","Neuroscience","Mutation","Alzheimer's disease","Medicine","Disease","Internal medicine","Biology","Genetics","Gene","Apoptosis","Hydrogen peroxide","Alzheimer’s disease","Caspase 3","DJ-1","Sildenafil","Amyloid-β"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-27T17:55:51.485204Z","pmid":null,"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":[]}