{"doi":"10.1101/2025.08.11.669740","title":"Modeling presynaptic inhibition by the amyloid precursor protein demonstrates one potential mechanism for preventing runaway synaptic modification in Alzheimer’s disease","abstract":"Abstract INTRODUCTION Previous simulations of Hebbian associative memory models inspired the malignant synaptic growth hypothesis of Alzheimer’s disease (AD), which suggests that cognitive impairments arise due to runaway synaptic modification resulting from poor separation between encoding and retrieval. METHODS We computationally model presynaptic inhibition by the recently identified interaction of soluble amyloid precursor protein (sAPPα) with the γ-aminobutyric acid type B receptor (GABA B R) as one potential biological mechanism which can enhance separation between encoding and retrieval. RESULTS Simulations predict that the dual effect of sAPPα on long-term potentiation and presynaptic inhibition of glutamatergic synapses maintains effective associative memory function and prevents runaway synaptic modification. Moreover, computational modeling predicts that sAPPα, which interacts with the 1a isoform of GABA B R, is more effective at stabilizing associative memory than the GABA B R agonist Baclofen. DISCUSSION Molecular mechanisms that enhance presynaptic inhibition, such as sAPPα-GABA B R1a signaling, are potential therapeutic targets for preventing cognitive impairments in AD.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":572788,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9557,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":257892,"name":"Michael E. Hasselmo","orcid":"0000-0002-9925-6377","position":1,"is_corresponding":false},{"id":1011779,"name":"Heather C. Rice","orcid":"0000-0002-5818-4338","position":2,"is_corresponding":false},{"id":1460267,"name":"Dylan Barber","orcid":null,"position":0,"is_corresponding":true}],"reference_count":109,"raw_metadata":null,"created_at":"2026-07-19T02:57:27.876396Z","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":[]}