Tetradecyl 2,3-Dihydroxybenzoate Improves Cognitive Function in AD Mice by Modulating Autophagy and Inflammation Through IPA and Hsc70 Targeting

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2024 Nov 9

PMID 39519271

Authors

Opeyemi B Fasina

Lanjie Li

Danni Chen

Meijuan Yi

Lan Xiang

Jianhua Qi

Affiliations

Soon will be listed here.

Abstract

Drug development for Alzheimer's 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-brain 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.

References

Swer N, Venkidesh B, Murali T, Mumbrekar K . Gut microbiota-derived metabolites and their importance in neurological disorders. Mol Biol Rep. 2022; 50(2):1663-1675. PMC: 9889412. DOI: 10.1007/s11033-022-08038-0. View

Sun J, Xu J, Yang B, Chen K, Kong Y, Fang N . Effect of Clostridium butyricum against Microglia-Mediated Neuroinflammation in Alzheimer's Disease via Regulating Gut Microbiota and Metabolites Butyrate. Mol Nutr Food Res. 2019; 64(2):e1900636. DOI: 10.1002/mnfr.201900636. View

Zhou L, Lu Z, Li L, Chen L, Qi J, Chen L . Pro-neurogenesis and anti-dementia properties of tetradecyl 2,3-dihydroxybenzoate through TrkA receptor-mediated signalling pathways. Int J Neuropsychopharmacol. 2014; 17(11):1847-61. DOI: 10.1017/S1461145714000558. View

Lomenick B, Hao R, Jonai N, Chin R, Aghajan M, Warburton S . Target identification using drug affinity responsive target stability (DARTS). Proc Natl Acad Sci U S A. 2009; 106(51):21984-9. PMC: 2789755. DOI: 10.1073/pnas.0910040106. View

Matt S, Allen J, Lawson M, Mailing L, Woods J, Johnson R . Butyrate and Dietary Soluble Fiber Improve Neuroinflammation Associated With Aging in Mice. Front Immunol. 2018; 9:1832. PMC: 6102557. DOI: 10.3389/fimmu.2018.01832. View

Sadovnikova I, Gureev A, Ignatyeva D, Gryaznova M, Chernyshova E, Krutskikh E . Nrf2/ARE Activators Improve Memory in Aged Mice via Maintaining of Mitochondrial Quality Control of Brain and the Modulation of Gut Microbiome. Pharmaceuticals (Basel). 2021; 14(7). PMC: 8308546. DOI: 10.3390/ph14070607. View

Cuervo A, Dice J . Age-related decline in chaperone-mediated autophagy. J Biol Chem. 2000; 275(40):31505-13. DOI: 10.1074/jbc.M002102200. View

Komura T, Aoki M, Kotoura S, Nishikawa Y . Protective effect of Lactococcus laudensis and Pediococcus parvulus against neuropathy due to amyloid-beta in Caenorhabditis elegans. Biomed Pharmacother. 2022; 155:113769. DOI: 10.1016/j.biopha.2022.113769. View

Fasina O, Wang J, Mo J, Osada H, Ohno H, Pan W . Gastrodin From Enhances Cognitive Function and Neuroprotection of AD Mice the Regulation of Gut Microbiota Composition and Inhibition of Neuron Inflammation. Front Pharmacol. 2022; 13:814271. PMC: 9201506. DOI: 10.3389/fphar.2022.814271. View

10.

Dinan T, Cryan J . The Microbiome-Gut-Brain Axis in Health and Disease. Gastroenterol Clin North Am. 2017; 46(1):77-89. DOI: 10.1016/j.gtc.2016.09.007. View

11.

Syed Y . Sodium Oligomannate: First Approval. Drugs. 2020; 80(4):441-444. DOI: 10.1007/s40265-020-01268-1. View

12.

Liao Y, Xing Q, Li Q, Zhang J, Pan R, Yuan Z . Astrocytes in depression and Alzheimer's disease. Front Med. 2021; 15(6):829-841. DOI: 10.1007/s11684-021-0875-0. View

13.

Ding Y, Zhu J, Zhang S, Zhang S, Wang C, Wang L . Tetradecyl 2,3-dihydroxybenzoate promotes functional recovery after spinal cord injury in adult rats. Genet Mol Res. 2016; 15(2). DOI: 10.4238/gmr.15028653. View

14.

Hawksworth J, Fernandez E, Gevaert K . A new generation of AD biomarkers: 2019 to 2021. Ageing Res Rev. 2022; 79:101654. DOI: 10.1016/j.arr.2022.101654. View

15.

Cheng L, Wang Y, Xiang L, Qi J . Heat Shock Cognate 70 kDa Protein Is the Target of Tetradecyl 2,3-Dihydroxybenzoate for Neuritogenic Effect in PC12 Cells. Biomedicines. 2021; 9(10). PMC: 8533567. DOI: 10.3390/biomedicines9101483. View

16.

Fakhoury M . Microglia and Astrocytes in Alzheimer's Disease: Implications for Therapy. Curr Neuropharmacol. 2017; 16(5):508-518. PMC: 5997862. DOI: 10.2174/1570159X15666170720095240. View

17.

Justo A, Suemoto C . The modulation of neuroinflammation by inducible nitric oxide synthase. J Cell Commun Signal. 2022; 16(2):155-158. PMC: 8891402. DOI: 10.1007/s12079-021-00663-x. View

18.

Jafari R, Almqvist H, Axelsson H, Ignatushchenko M, Lundback T, Nordlund P . The cellular thermal shift assay for evaluating drug target interactions in cells. Nat Protoc. 2014; 9(9):2100-22. DOI: 10.1038/nprot.2014.138. View

19.

Liao Z, Wang B, Liu W, Xu Q, Hou L, Song J . Dysfunction of chaperone-mediated autophagy in human diseases. Mol Cell Biochem. 2021; 476(3):1439-1454. DOI: 10.1007/s11010-020-04006-z. View

20.

Mackey-Alfonso S, Butler M, Taylor A, Williams-Medina A, Muscat S, Fu H . Short-term high fat diet impairs memory, exacerbates the neuroimmune response, and evokes synaptic degradation via a complement-dependent mechanism in a mouse model of Alzheimer's disease. Brain Behav Immun. 2024; 121:56-69. DOI: 10.1016/j.bbi.2024.07.021. View