{"doi":"10.1186/s40478-024-01799-8","title":"Biomarker evidence of early vision and rod energy-linked pathophysiology benefits from very low dose DMSO in 5xFAD mice","abstract":"Here, we test whether early visual and OCT rod energy-linked biomarkers indicating pathophysiology in nicotinamide nucleotide transhydrogenase (Nnt)-null 5xFAD mice also occur in Nnt-intact 5xFAD mice and whether these biomarkers can be pharmacologically treated. Four-month-old wild-type or 5xFAD C57BL/6 substrains with either a null (B6J) Nnt or intact Nnt gene (B6NTac) and 5xFAD B6J mice treated for one month with either R-carvedilol + vehicle or only vehicle (0.01% DMSO) were studied. The contrast sensitivity (CS), external limiting membrane-retinal pigment epithelium (ELM-RPE) thickness (a proxy for low pH-triggered water removal), profile shape of the hyperreflective band just posterior to the ELM (i.e., the mitochondrial configuration within photoreceptors per aspect ratio [MCP/AR]), and retinal laminar thickness were measured. Both wild-type substrains showed similar visual performance indices and dark-evoked ELM-RPE contraction. The lack of a light-dark change in B6NTac MCP/AR, unlike in B6J mice, is consistent with relatively greater mitochondrial efficiency. 5xFAD B6J mice, but not 5xFAD B6NTac mice, showed lower-than-WT CS. Light-adapted 5xFAD substrains both showed abnormal ELM-RPE contraction and greater-than-WT MCP/AR contraction. The inner retina and superior outer retina were thinner. Treating 5xFAD B6J mice with R-carvedilol + DMSO or DMSO alone corrected CS and ELM-RPE contraction but not supernormal MCP/AR contraction or laminar thinning. These results provide biomarker evidence for prodromal photoreceptor mitochondrial dysfunction/oxidative stress/oxidative damage, which is unrelated to visual performance, as well as the presence of the Nnt gene. This pathophysiology is druggable in 5xFAD mice.","journal":"Acta Neuropathologica Communications","year":2024,"id":473461,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9613,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1142411,"name":"Anuhya Paruchuri","orcid":null,"position":1,"is_corresponding":false},{"id":1142412,"name":"Josh Stanek","orcid":null,"position":2,"is_corresponding":false},{"id":1309804,"name":"Mura Abdul-Nabi","orcid":null,"position":3,"is_corresponding":false},{"id":402011,"name":"Robert H. Podolsky","orcid":"0000-0003-3547-8859","position":4,"is_corresponding":false},{"id":1309805,"name":"Abner Heredia Bustos","orcid":null,"position":5,"is_corresponding":false},{"id":402012,"name":"Karen Lins Childers","orcid":"0000-0002-7645-1583","position":6,"is_corresponding":false},{"id":455504,"name":"Geoffrey G. Murphy","orcid":"0000-0003-3691-1722","position":7,"is_corresponding":false},{"id":772465,"name":"Katherine A. Stangis","orcid":"0009-0009-6071-0366","position":8,"is_corresponding":false},{"id":402016,"name":"Robin Roberts","orcid":"0009-0001-1705-0747","position":9,"is_corresponding":false},{"id":402008,"name":"Bruce A. Berkowitz","orcid":"0000-0003-0291-2209","position":0,"is_corresponding":true}],"reference_count":131,"raw_metadata":null,"created_at":"2026-07-19T02:06:04.967429Z","pmid":"38822433","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":[]}