{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T03:03:54Z","timestamp":1778641434781,"version":"3.51.4"},"reference-count":42,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,3,20]],"date-time":"2025-03-20T00:00:00Z","timestamp":1742428800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key R&amp;D Program of China","doi-asserted-by":"publisher","award":["2022YFE0104000"],"award-info":[{"award-number":["2022YFE0104000"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In previous studies, we isolated a series of novel gentisides with nerve growth factor (NGF)-mimic activities from Gentiana rigescens Franch and conducted continuous structure\u2013activity relationship (SAR) studies. Recently, a lead compound named TBG096 was discovered with significant NGF-mimic activity, low toxicity, and ability to pass through the blood\u2013brain barrier (BBB). At the cell level, TBG096 exerts NGF-mimic activity by regulation of heat-shock cognate protein 70 (Hsc70) and downstream proteins. Subsequently, high-fat diet (HFD)-induced Alzheimer disease (AD) mouse models were used to evaluate the anti-AD efficacy of the compound. TBG096 significantly improved the memory dysfunction of AD mice at doses of 0.1, 5, and 20 mg\/kg, respectively. In order to elucidate the mechanism of action of the compound against AD, the RNA-sequence analysis of transcriptomics, quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence staining, and Western blot analysis were performed using animal samples. TBG096 significantly increased the expression of the Wnt gene family (Wnt10b, Wnt5a, and Wnt1) and the number of mature neurons and newborn neurons in the hippocampus and cerebral cortex of AD mice, respectively. At the same time, it reduced the activity of microglia, astrocyte cells, and expression of inducible nitric oxide synthase (INOS) in the brain. Moreover, this compound significantly increased phosphorylated-adenosine 5\u2032-monophosphate-activated protein kinase (AMPK), Hsc70, and lysosomal-associated membrane protein 2a (LAMP2A) and decreased the expression of hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), amyloid precursor protein (APP), microtubule-associated protein tau (Tau), phosphoryl-Tau, and \u03b2-amyloid (A\u03b2) at the protein level. These results suggest that TBG096 produced the NGF-mimic activity and the anti-AD effect via promoting neurogenesis and modification of the Hsc70\/HK2\/PKM2\/LAMP2A signaling pathway, proposing a potential novel approach to counteracting cognitive decline by developing small molecules that promote neurogenesis and the Hsc70 signaling pathway.<\/jats:p>","DOI":"10.3390\/ijms26062804","type":"journal-article","created":{"date-parts":[[2025,3,20]],"date-time":"2025-03-20T07:59:54Z","timestamp":1742457594000},"page":"2804","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["TBG096 Ameliorates Memory Deficiency in AD Mouse Model via Promoting Neurogenesis and Regulation of Hsc70\/HK2\/PKM2\/LAMP2A Signaling Pathway"],"prefix":"10.3390","volume":"26","author":[{"given":"Danni","family":"Chen","sequence":"first","affiliation":[{"name":"College of Pharmaceutical Sciences, Zhejiang University, Yu Hang Tang Road 866, Hangzhou 310058, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Opeyemi B.","family":"Fasina","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Sciences, Zhejiang University, Yu Hang Tang Road 866, Hangzhou 310058, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2540-7089","authenticated-orcid":false,"given":"Jiahui","family":"Lin","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Sciences, Zhejiang University, Yu Hang Tang Road 866, Hangzhou 310058, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiayuan","family":"Zeng","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Sciences, Zhejiang University, Yu Hang Tang Road 866, Hangzhou 310058, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Majid","family":"Manzoor","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Sciences, Zhejiang University, Yu Hang Tang Road 866, Hangzhou 310058, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8776-9661","authenticated-orcid":false,"given":"Hiroshi","family":"Ohno","sequence":"additional","affiliation":[{"name":"RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehirocho, Tsutumiku, Yokohama 230-0045, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6595-2836","authenticated-orcid":false,"given":"Lan","family":"Xiang","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Sciences, Zhejiang University, Yu Hang Tang Road 866, Hangzhou 310058, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianhua","family":"Qi","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Sciences, Zhejiang University, Yu Hang Tang Road 866, Hangzhou 310058, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.pharmthera.2011.12.002","article-title":"Pharmacotherapies for Alzheimer\u2019s disease: Beyond cholinesterase inhibitors","volume":"134","author":"Tayeb","year":"2012","journal-title":"Pharmacol. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s40035-024-00432-x","article-title":"Updates in Alzheimer\u2019s disease: From basic research to diagnosis and therapies","volume":"13","author":"Liu","year":"2024","journal-title":"Transl. Neurodegener."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"eaan8821","DOI":"10.1126\/science.aan8821","article-title":"Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer\u2019s mouse model","volume":"361","author":"Choi","year":"2018","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1016\/j.apsb.2021.12.009","article-title":"Pharmacological modulation of autophagy for Alzheimer\u2019s disease therapy: Opportunities and obstacles","volume":"12","author":"Deng","year":"2022","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.phrs.2018.10.028","article-title":"Painless Nerve Growth Factor: A TrkA biased agonist mediating a broad neuroprotection via its actions on microglia cells","volume":"139","author":"Cattaneo","year":"2019","journal-title":"Pharmacol. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s13024-016-0119-y","article-title":"Neurotrophic factor small-molecule mimetics mediated neuroregeneration and synaptic repair: Emerging therapeutic modality for Alzheimer\u2019s disease","volume":"11","author":"Kazim","year":"2016","journal-title":"Mol. Neurodegener."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2806","DOI":"10.1093\/brain\/awab460","article-title":"Ultrasound delivery of a TrkA agonist confers neuroprotection to Alzheimer-associated pathologies","volume":"145","author":"Xhima","year":"2022","journal-title":"Brain"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1126\/science.aav6885","article-title":"Adult neurogenesis in mammals","volume":"364","author":"Gage","year":"2019","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/j.stemcr.2021.01.019","article-title":"Adult hippocampal neurogenesis in aging and Alzheimer\u2019s disease","volume":"16","author":"Babcock","year":"2021","journal-title":"Stem Cell Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1038\/nature04108","article-title":"Wnt signalling regulates adult hippocampal neurogenesis","volume":"437","author":"Lie","year":"2005","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/s41586-023-05972-2","article-title":"A small-molecule PI3K\u03b1 activator for cardioprotection and neuroregeneration","volume":"618","author":"Gong","year":"2023","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1038\/s41580-024-00757-5","article-title":"Mechanisms of autophagy-lysosome dysfunction in neurodegenerative diseases","volume":"25","author":"Nixon","year":"2024","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/j.biopsych.2019.05.008","article-title":"Autophagy dysfunction in Alzheimer\u2019s disease: Mechanistic insights and new therapeutic opportunities","volume":"87","author":"Curtis","year":"2020","journal-title":"Biol. Psychiatry"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1016\/j.cell.2019.05.056","article-title":"LC3-associated endocytosis facilitates \u03b2-Amyloid clearance and mitigates neurodegeneration in murine Alzheimer\u2019s disease","volume":"178","author":"Heckmann","year":"2019","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/j.tcb.2012.05.006","article-title":"Chaperone-mediated autophagy: A unique way to enter the lysosome world","volume":"22","author":"Kaushik","year":"2012","journal-title":"Trends Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/0968-0004(90)90019-8","article-title":"Peptide sequences that target cytosolic proteins for lysosomal proteolysis","volume":"15","author":"Dice","year":"1990","journal-title":"Trends Biochem. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1937","DOI":"10.4161\/auto.26448","article-title":"HSPA8\/HSC70 chaperoneprotein: Structure, function, and chemical targeting","volume":"9","author":"Stricher","year":"2013","journal-title":"Autophagy"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/nrm3150","article-title":"Chaperone-mediated autophagy: Dice\u2019s \u2018wild\u2019 idea about lysosomal selectivity","volume":"12","author":"Cuervo","year":"2011","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1677\/JME-08-0116","article-title":"From hatching to dispatching: The multiple cellular roles of the Hsp70 molecular chaperone machinery","volume":"42","author":"Meimaridou","year":"2009","journal-title":"J. Mol. Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1007\/s13238-021-00858-3","article-title":"Metformin activates chaperone-mediated autophagy and improves disease pathologies in an Alzheimer disease mouse model","volume":"12","author":"Xu","year":"2021","journal-title":"Protein Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"16798","DOI":"10.1074\/jbc.M110.113753","article-title":"Hsc70 rapidly engages tau after microtubule destabilization","volume":"285","author":"Jinwal","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Reilly, A.M., Tsai, A.P., Lin, P.B., Ericsson, A.C., Oblak, A.L., and Ren, H. (2020). Metabolic defects caused by high-fat diet modify disease risk through inflammatory and amyloidogenic pathways in a mouse model of Alzheimer\u2019s disease. Nutrients, 12.","DOI":"10.3390\/nu12102977"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1986","DOI":"10.1002\/cmdc.201100348","article-title":"Structure-activity relationships of neuritogenic gentiside derivatives","volume":"6","author":"Luo","year":"2011","journal-title":"ChemMedChem"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Cheng, L., Wang, Y., Xiang, L., and Qi, J. (2021). Heat shock cognate 70 kDa protein is the target of tetradecyl 2,3-dihydroxybenzoate for neuritogenic effect in PC12 cells. Biomedicines, 9.","DOI":"10.3390\/biomedicines9101483"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1038\/s41557-019-0412-9","article-title":"Use of \u03b1-trifluoromethyl carbanions for palladium-catalysed asymmetric cycloadditions","volume":"12","author":"Trost","year":"2020","journal-title":"Nat. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1080\/15548627.2015.1124226","article-title":"AMPK-dependent phosphorylation of lipid droplet protein PLIN2 triggers its degradation by CMA","volume":"12","author":"Kaushik","year":"2016","journal-title":"Autophagy"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1177\/0271678X17746186","article-title":"Apolipoprotein E4 mediates insulin resistance-associated cerebrovascular dysfunction and the post-prandial response","volume":"39","author":"Johnson","year":"2019","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1126\/science.8420006","article-title":"Blood-brain barrier penetration and in vivo activity of an NGF conjugate","volume":"259","author":"Friden","year":"1993","journal-title":"Science"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Cao, G., Gong, T., Du, Y., Wang, Y., Ge, T., and Liu, J. (2022). Mechanism of metformin regulation in central nervous system: Progression and future perspectives. Biomed. Pharmacother., 156.","DOI":"10.1016\/j.biopha.2022.113686"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1007\/s00125-015-3844-9","article-title":"Metformin and the gastrointestinal tract","volume":"59","author":"McCreight","year":"2016","journal-title":"Diabetologia"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"81","DOI":"10.2165\/11534750-000000000-00000","article-title":"Clinical pharmacokinetics of metformin","volume":"50","author":"Graham","year":"2011","journal-title":"Clin. Pharmacokinet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.lfs.2019.04.009","article-title":"In vivo pharmacodynamic and pharmacokinetic effects of metformin mediated by the gut microbiota in rats","volume":"226","author":"Wu","year":"2019","journal-title":"Life Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"eabo7421","DOI":"10.1126\/sciadv.abo7421","article-title":"A genetic variant of the Wnt receptor LRP6 accelerates synapse degeneration during aging and in Alzheimer\u2019s disease","volume":"9","author":"Jones","year":"2023","journal-title":"Sci. Adv."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/j.jalz.2016.02.010","article-title":"Neuroinflammation in Alzheimer\u2019s disease: Current evidence and future directions","volume":"12","author":"Calsolaro","year":"2016","journal-title":"Alzheimers. Dement."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1186\/1750-1326-6-85","article-title":"Adult hippocampal neurogenesis and its role in Alzheimer\u2019s disease","volume":"6","author":"Mu","year":"2011","journal-title":"Mol. Neurodegener."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1016\/j.cell.2016.10.041","article-title":"How old brains got new neurons","volume":"167","author":"Gage","year":"2016","journal-title":"Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s40035-021-00270-1","article-title":"The role of pathological tau in synaptic dysfunction in Alzheimer\u2019s diseases","volume":"10","author":"Wu","year":"2021","journal-title":"Transl. Neurodegener."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6283","DOI":"10.1111\/jcmm.14514","article-title":"Cucurbitacin B induces neurogenesis in PC12 cells and protects memory in APP\/PS1 mice","volume":"23","author":"Li","year":"2019","journal-title":"J. Cell Mol. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"154730","DOI":"10.1016\/j.phymed.2023.154730","article-title":"A new gentiopicroside derivative improves cognitive deficits of AD mice via activation of Wnt signaling pathway and regulation of gut microbiota homeostasis","volume":"113","author":"Wang","year":"2023","journal-title":"Phytomedicine"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Fasina, O.B., Li, L., Chen, D., Yi, M., Xiang, L., and Qi, J. (2024). Tetradecyl 2,3-dihydroxybenzoate improves cognitive function in ad mice by modulating autophagy and inflammation through IPA and Hsc70 targeting. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252111719"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1038\/nn.4030","article-title":"Host microbiota constantly control maturation and function of microglia in the CNS","volume":"18","author":"Erny","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e2400340","DOI":"10.1002\/advs.202400340","article-title":"Zosuquidar promotes antitumor immunity by inducing autophagic degradation of PD-L1","volume":"11","author":"Ding","year":"2024","journal-title":"Adv. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/6\/2804\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:57:06Z","timestamp":1760029026000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/6\/2804"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,20]]},"references-count":42,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["ijms26062804"],"URL":"https:\/\/doi.org\/10.3390\/ijms26062804","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,20]]}}}