{"doi":"10.1016/j.nbd.2023.106285","title":"Novel systemic delivery of a peptide-conjugated antisense oligonucleotide to reduce α-synuclein in a mouse model of Alzheimer's disease","abstract":"Neurodegenerative disorders of aging are characterized by the progressive accumulation of proteins such as α-synuclein (α-syn) and amyloid beta (Aβ). Misfolded and aggregated α-syn has been implicated in neurological disorders such as Parkinson's disease, and Dementia with Lewy Bodies, but less so in Alzheimer's Disease (AD), despite the fact that accumulation of α-syn has been confirmed in over 50% of postmortem brains neuropathologically diagnosed with AD. To date, no therapeutic strategy has effectively or consistently downregulated α-syn in AD. Here we tested the hypothesis that by using a systemically-delivered peptide (ApoB11) bound to a modified antisense oligonucleotide against α-syn (ASO-α-syn), we can downregulate α-syn expression in an AD mouse model and improve behavioral and neuropathologic phenotypes. Our results demonstrate that monthly systemic treatment with of ApoB11:ASO α-syn beginning at 6 months of age reduces expression of α-synuclein in the brains of 9-month-old AD mice. Downregulation of α-syn also led to reduction in Aβ plaque burden, prevented neuronal loss and astrogliosis. Furthermore, we found that AD mice treated with ApoB11:ASO α-syn had greatly improved hippocampal and spatial memory function in comparison to their control counterparts. Collectively, our data supports the reduction of α-syn through use of systemically-delivered ApoB11:ASO α-syn as a promising future disease-modifying therapeutic for AD.","journal":"Neurobiology of Disease","year":2023,"id":330513,"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":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.951,"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":956502,"name":"Rijwan Uddin Ahammad","orcid":null,"position":1,"is_corresponding":false},{"id":96601,"name":"Brian Spencer","orcid":"0000-0002-7486-1941","position":2,"is_corresponding":false},{"id":524160,"name":"Chengbiao Wu","orcid":"0000-0002-3660-088X","position":3,"is_corresponding":false},{"id":58514,"name":"Eliezer Masliah","orcid":"0000-0002-2117-5569","position":4,"is_corresponding":false},{"id":230262,"name":"Robert A. Rissman","orcid":"0000-0001-9245-8278","position":5,"is_corresponding":false},{"id":1054267,"name":"André Leitão","orcid":"0000-0003-0500-3545","position":0,"is_corresponding":true}],"reference_count":71,"raw_metadata":null,"created_at":"2026-07-19T01:09:10.120703Z","pmid":"37690676","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":[]}