Brain Delivery of Quercetin-loaded Exosomes Improved Cognitive Function in AD Mice by Inhibiting Phosphorylated Tau-mediated Neurofibrillary Tangles

Overview

Journal Drug Deliv

Specialty Pharmacology

Date 2020 May 14

PMID 32397764

Citations 88

Authors

Yao Qi

Lin Guo

Yibing Jiang

Yijie Shi

Haijuan Sui

Liang Zhao

Affiliations

Soon will be listed here.

Abstract

It is reported that quercetin (Que) can prevent tau pathology and induce neuroprotection by improving cognitive and functional symptoms in the treatment of Alzheimer's disease (AD). However, its clinical application has been limited due to its poor brain targeting and bioavailability. Exosomes are considered as cargo carriers for intercellular communication and especially serve as a natural and important drug brain delivery platform for achieving better treatment of central neurological diseases. Here, we developed plasma exosomes (Exo) loaded with Que (Exo-Que) to improve the drug bioavailability, enhance the brain targeting of Que and potently ameliorate cognitive dysfunction in okadaic acid (OA)-induced AD mice. Our results showed that Exo-Que improved brain targeting of Que as well as significantly enhanced bioavailability of Que. Furthermore, compared with free Que, Exo-Que better relieved the symptoms of AD by inhibiting cyclin-dependent kinase 5 (CDK5)-mediated phosphorylation of Tau and reducing formation of insoluble neurofibrillary tangles (NFTs), suggesting its therapeutic potential for better treatment of AD.

Citing Articles

Non-pharmacological treatment of Alzheimer's disease: an update.

Wang S, Xu H, Liu G, Chen L Front Aging Neurosci. 2025; 17:1527242.

PMID: 40018518 PMC: 11865074. DOI: 10.3389/fnagi.2025.1527242.

Natural products against tau hyperphosphorylation-induced aggregates: Potential therapies for Alzheimer's disease.

Basurto-Islas G, Diaz M, Ocampo L, Martinez-Herrera M, Lopez-Camacho P Arch Pharm (Weinheim). 2025; 358(1):e2400721.

PMID: 39888017 PMC: 11781347. DOI: 10.1002/ardp.202400721.

Human Plasma-Derived Exosomes: A Promising Carrier System for the Delivery of Hydroxyurea to Combat Breast Cancer.

Khalid W, Aslam A, Ahmed N, Sarfraz M, Khan J, Mohsin S AAPS PharmSciTech. 2025; 26(1):42.

PMID: 39843767 DOI: 10.1208/s12249-024-03028-w.

Secretome - the role of extracellular vesicles in the pathogenesis and therapy of neurodegenerative diseases.

Sulek A Postep Psychiatr Neurol. 2024; 33(3):147-162.

PMID: 39678458 PMC: 11635433. DOI: 10.5114/ppn.2024.144686.

Exosome Cargo in Neurodegenerative Diseases: Leveraging Their Intercellular Communication Capabilities for Biomarker Discovery and Therapeutic Delivery.

Zhang S, Yang Y, Lv X, Zhou X, Zhao W, Meng L Brain Sci. 2024; 14(11).

PMID: 39595812 PMC: 11591915. DOI: 10.3390/brainsci14111049.

References

Lane C, Hardy J, Schott J . Alzheimer's disease. Eur J Neurol. 2017; 25(1):59-70. DOI: 10.1111/ene.13439. View

Ramalho M, Andrade S, Loureiro J, Pereira M . Nanotechnology to improve the Alzheimer's disease therapy with natural compounds. Drug Deliv Transl Res. 2019; 10(2):380-402. DOI: 10.1007/s13346-019-00694-3. View

Shen X, Luo T, Li S, Ting O, He F, Xu J . Quercetin inhibits okadaic acid-induced tau protein hyperphosphorylation through the Ca2+‑calpain‑p25‑CDK5 pathway in HT22 cells. Int J Mol Med. 2017; 41(2):1138-1146. DOI: 10.3892/ijmm.2017.3281. View

Epperly T, Dunay M, Boice J . Alzheimer Disease: Pharmacologic and Nonpharmacologic Therapies for Cognitive and Functional Symptoms. Am Fam Physician. 2017; 95(12):771-778. View

Blanc L, de Gassart A, Geminard C, Bette-Bobillo P, Vidal M . Exosome release by reticulocytes--an integral part of the red blood cell differentiation system. Blood Cells Mol Dis. 2005; 35(1):21-6. DOI: 10.1016/j.bcmd.2005.04.008. View

Kuo Y, Chen C, Rajesh R . Optimized liposomes with transactivator of transcription peptide and anti-apoptotic drugs to target hippocampal neurons and prevent tau-hyperphosphorylated neurodegeneration. Acta Biomater. 2019; 87:207-222. DOI: 10.1016/j.actbio.2019.01.065. View

Luo Z, Li F, Liu Y, Rao S, Yin H, Huang J . Aptamer-functionalized exosomes from bone marrow stromal cells target bone to promote bone regeneration. Nanoscale. 2019; 11(43):20884-20892. DOI: 10.1039/c9nr02791b. View

Xiong Y, Chen L, Yan C, Zhou W, Endo Y, Liu J . Circulating Exosomal miR-20b-5p Inhibition Restores Wnt9b Signaling and Reverses Diabetes-Associated Impaired Wound Healing. Small. 2019; 16(3):e1904044. DOI: 10.1002/smll.201904044. View

Zheng Y, He R, Wang P, Shi Y, Zhao L, Liang J . Exosomes from LPS-stimulated macrophages induce neuroprotection and functional improvement after ischemic stroke by modulating microglial polarization. Biomater Sci. 2019; 7(5):2037-2049. DOI: 10.1039/c8bm01449c. View

10.

Fais S, ODriscoll L, Borras F, Buzas E, Camussi G, Cappello F . Evidence-Based Clinical Use of Nanoscale Extracellular Vesicles in Nanomedicine. ACS Nano. 2016; 10(4):3886-99. DOI: 10.1021/acsnano.5b08015. View

11.

Tian T, Zhang H, He C, Fan S, Zhu Y, Qi C . Surface functionalized exosomes as targeted drug delivery vehicles for cerebral ischemia therapy. Biomaterials. 2017; 150:137-149. DOI: 10.1016/j.biomaterials.2017.10.012. View

12.

Vinayak M, Maurya A . Quercetin Loaded Nanoparticles in Targeting Cancer: Recent Development. Anticancer Agents Med Chem. 2019; 19(13):1560-1576. DOI: 10.2174/1871520619666190705150214. View

13.

Su C, Li H, Shi Y, Wang G, Liu L, Zhao L . Carboxymethyl-β-cyclodextrin conjugated nanoparticles facilitate therapy for folate receptor-positive tumor with the mediation of folic acid. Int J Pharm. 2014; 474(1-2):202-11. DOI: 10.1016/j.ijpharm.2014.08.026. View

14.

Xu A, Yang Y, Sun Y, Zhang C . Exogenous brain-derived neurotrophic factor attenuates cognitive impairment induced by okadaic acid in a rat model of Alzheimer's disease. Neural Regen Res. 2018; 13(12):2173-2181. PMC: 6199930. DOI: 10.4103/1673-5374.241471. View

15.

Qu M, Lin Q, Huang L, Fu Y, Wang L, He S . Dopamine-loaded blood exosomes targeted to brain for better treatment of Parkinson's disease. J Control Release. 2018; 287:156-166. DOI: 10.1016/j.jconrel.2018.08.035. View

16.

Zenaro E, Piacentino G, Constantin G . The blood-brain barrier in Alzheimer's disease. Neurobiol Dis. 2016; 107:41-56. PMC: 5600438. DOI: 10.1016/j.nbd.2016.07.007. View

17.

Zeb A, Son M, Yoon S, Kim J, Park S, Lee K . Computational Simulations Identified Two Candidate Inhibitors of Cdk5/p25 to Abrogate Tau-associated Neurological Disorders. Comput Struct Biotechnol J. 2019; 17:579-590. PMC: 6495220. DOI: 10.1016/j.csbj.2019.04.010. View

18.

Re F, Gregori M, Masserini M . Nanotechnology for neurodegenerative disorders. Maturitas. 2012; 73(1):45-51. DOI: 10.1016/j.maturitas.2011.12.015. View

19.

Lener T, Gimona M, Aigner L, Borger V, Buzas E, Camussi G . Applying extracellular vesicles based therapeutics in clinical trials - an ISEV position paper. J Extracell Vesicles. 2016; 4:30087. PMC: 4698466. DOI: 10.3402/jev.v4.30087. View

20.

Yamazaki Y, Kanekiyo T . Blood-Brain Barrier Dysfunction and the Pathogenesis of Alzheimer's Disease. Int J Mol Sci. 2017; 18(9). PMC: 5618614. DOI: 10.3390/ijms18091965. View