{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:12:57Z","timestamp":1792793577137,"version":"4.5.0"},"reference-count":51,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T00:00:00Z","timestamp":1730332800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Key R&amp;D Program of China","award":["2022YFE0104000"],"award-info":[{"award-number":["2022YFE0104000"]}]},{"name":"National Key R&amp;D Program of China","award":["2019YFE0100700"],"award-info":[{"award-number":["2019YFE0100700"]}]},{"name":"National Key R&amp;D Program of China","award":["22177102"],"award-info":[{"award-number":["22177102"]}]},{"DOI":"10.13039\/501100001809","name":"NSFC","doi-asserted-by":"publisher","award":["2022YFE0104000"],"award-info":[{"award-number":["2022YFE0104000"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"NSFC","doi-asserted-by":"publisher","award":["2019YFE0100700"],"award-info":[{"award-number":["2019YFE0100700"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"NSFC","doi-asserted-by":"publisher","award":["22177102"],"award-info":[{"award-number":["22177102"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Drug development for Alzheimer\u2019s disease (AD) treatment is challenging due to its complex pathogenesis. Tetradecyl 2,3-dihydroxybenzoate (ABG-001), a leading compound identified in our prior research, has shown promising NGF-mimicking activity and anti-aging properties. In the present study, both high-fat diet (HFD)-induced AD mice and naturally aging AD mice were used to evaluate anti-AD effects. Meanwhile, RNA-sequences, Western blotting, immunofluorescence staining, enzyme-linked immunosorbent assay (ELISA), cellular thermal shift assay (CETSA), drug affinity-responsive target stability (DARTS) assay, construction of expression plasmid and protein purification, surface plasmon resonance (SPR) analysis, and 16S rRNA sequence analysis were used to identify the target protein of ABG-001 and clarify the mechanism of action for this molecule. ABG-001 effectively mitigates the memory dysfunction in both HFD-induced AD mice and naturally aging AD mice. The therapeutic effect of ABG-001 is attributed to its ability to promote neurogenesis, activate chaperone-mediated autophagy (CMA), and reduce neuronal inflammation. Additionally, ABG-001 positively influenced the gut microbiota, enhancing the production of indole-3-propionic acid (IPA), which is capable of crossing the blood\u2013brain barrier (BBB) and contributes to neuronal regeneration. Furthermore, our research revealed that IPA, linked to the anti-AD properties of ABG-001, targets the heat shock cognate 70 kDa protein (Hsc70) and regulates the Hsc70\/PKM2\/HK2\/LC3 and FOXO3a\/SIRT1 signaling pathways. ABG-001 improves the memory dysfunction of AD mice by modulating autophagy and inflammation through IPA and Hsc70 targeting. These findings offer a novel approach for treating neurodegenerative diseases, focusing on the modification of the gut microbiota and metabolites coupled with anti-aging strategies.<\/jats:p>","DOI":"10.3390\/ijms252111719","type":"journal-article","created":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T08:44:04Z","timestamp":1730364244000},"page":"11719","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Tetradecyl 2,3-Dihydroxybenzoate Improves Cognitive Function in AD Mice by Modulating Autophagy and Inflammation Through IPA and Hsc70 Targeting"],"prefix":"10.3390","volume":"25","author":[{"given":"Opeyemi B.","family":"Fasina","sequence":"first","affiliation":[{"name":"College of Pharmaceutical Science, Zhejiang University, 866 Yu Hang Road, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lanjie","family":"Li","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Science, Zhejiang University, 866 Yu Hang Road, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danni","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Science, Zhejiang University, 866 Yu Hang Road, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meijuan","family":"Yi","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Science, Zhejiang University, 866 Yu Hang Road, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6595-2836","authenticated-orcid":false,"given":"Lan","family":"Xiang","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Science, Zhejiang University, 866 Yu Hang Road, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhua","family":"Qi","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Science, Zhejiang University, 866 Yu Hang Road, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"101654","DOI":"10.1016\/j.arr.2022.101654","article-title":"A new generation of AD biomarkers: 2019 to 2021","volume":"79","author":"Hawksworth","year":"2022","journal-title":"Ageing Res. 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