biostudies-literatureBaek SHFuture Medicine 20*30 Project of Samsung Medical CenterNational Research Foundation of KoreaMinistry of Oceans and Fisheries' R&D project, Koreae2407812https://www.ebi.ac.uk/biostudies/studies/S-EPMC11848596biostudies-literatureUnknown12(8)β-secretase (BACE1) is instrumental in amyloid-β (Aβ) production, with overexpression noted in Alzheimer's disease (AD) neuropathology. The interaction of Aβ with the receptor for advanced glycation endproducts (RAGE) facilitates cerebral uptake of Aβ and exacerbates its neurotoxicity and neuroinflammation, further augmenting BACE1 expression. Given the limitations of previous BACE1 inhibition efforts, the study explores reducing BACE1 expression to mitigate AD pathology. The research reveals that the anticancer agent 6-thioguanosine (6-TG) markedly diminishes BACE1 expression without eliciting cytotoxicity while enhancing microglial phagocytic activity, and ameliorate cognitive impairments with reducing Aβ accumulation in AD mice. Leveraging advanced deep learning-based tool for target idAdvanced science (Weinheim, Baden-Wurttemberg, Germany)A Novel RAGE Modulator Induces Soluble RAGE to Reduce BACE1 Expression in Alzheimer's Disease.PMC11848596No. SMX1240561RS-2024-00399237RS-2019-NR040057NRF-2022R1I1A1A01072791RS-2021-KS211513RS-2024-00345742Kim DCho YKim JPSeo SWPark JKim ELee MPark SBaek SHYoon HYun YKim YChoi YJo DGJung SHong SKang KJung YKfalseA Novel RAGE Modulator Induces Soluble RAGE to Reduce BACE1 Expression in Alzheimer's Disease.β-secretase (BACE1) is instrumental in amyloid-β (Aβ) production, with overexpression noted in Alzheimer's disease (AD) neuropathology. The interaction of Aβ with the receptor for advanced glycation endproducts (RAGE) facilitates cerebral uptake of Aβ and exacerbates its neurotoxicity and neuroinflammation, further augmenting BACE1 expression. Given the limitations of previous BACE1 inhibition efforts, the study explores reducing BACE1 expression to mitigate AD pathology. The research reveals that the anticancer agent 6-thioguanosine (6-TG) markedly diminishes BACE1 expression without eliciting cytotoxicity while enhancing microglial phagocytic activity, and ameliorate cognitive impairments with reducing Aβ accumulation in AD mice. Leveraging advanced deep learning-based tool for target id2025-01-01T00:00:00Z2025 Feb2025-04-18T13:25:47.565Z2025-04-04T09:09:33.948ZS-EPMC118485963975592710.1002/advs.202407812