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Cited by 239Alzheimer's disease research and treatmentsExtracellular vesicles in diseaseNanoparticle-Based Drug Delivery

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Brain delivery of quercetin-loaded exosomes improved cognitive function in AD mice by inhibiting phosphorylated tau-mediated neurofibrillary tangles

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Qi, Yao, Guo, Lin, Jiang, Yibing, Shi, Yijie, Sui, Haijuan, Zhao, Liang·2020·Drug Delivery
DOI 10.1080/10717544.2020.1762262PMC PMC7269046
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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.

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Figures

Figure 1. Primary hypothesis of this study. Exo-Que enhanced the bioavailability and achieved brain targeting in vivo. Exo-Que improved cognitive and functional symptoms in OA-induced AD mice by inhibiting CDK5-mediated phosphorylation of Tau and reducing NFTs.
Figure 1. Primary hypothesis of this study. Exo-Que enhanced the bioavailability and achieved brain targeting in vivo. Exo-Que improved cognitive and functional symptoms in OA-induced AD mice by inhibiting CDK5-mediated phosphorylation of Tau and reducing NFTs.CC BY · PubMed Central
Figure 2. Experimental design for the animal study.
Figure 2. Experimental design for the animal study.CC BY · PubMed Central
Figure 3. Characterization determination of Exo and Exo-Que. (A) Morphology of Exo and Exo-Que by AFM. (B) Particle size distribution of Exo and Exo-Que. (C) Detection of exosomal specific markers by western blot.
Figure 3. Characterization determination of Exo and Exo-Que. (A) Morphology of Exo and Exo-Que by AFM. (B) Particle size distribution of Exo and Exo-Que. (C) Detection of exosomal specific markers by western blot.CC BY · PubMed Central
Figure 4. Exo-Que enhanced the bioavailability of Que in vivo. (A) The plasma concentration–time curve and fitted PK parameters of Que and Exo-Que after single i.v. administration of Que and Exo-Que at the concentration of Que (12 mg/kg). Data are expressed as means ± SD (n = 3). *p < 0.05 and **p < 0.01. (B) H&E staining of heart, liver, spleen, lung, and kidney tissue sections of rats at 7 day after i.v. daily administering a single dose of 1 mL of saline and 1 mL of various Que formulations at 12 mg/kg. The scale bar is 200 μm and applies to all figure parts.
Figure 4. Exo-Que enhanced the bioavailability of Que in vivo. (A) The plasma concentration–time curve and fitted PK parameters of Que and Exo-Que after single i.v. administration of Que and Exo-Que at the concentration of Que (12 mg/kg). Data are expressed as means ± SD (n = 3). *p < 0.05 and **p < 0.01. (B) H&E staining of heart, liver, spleen, lung, and kidney tissue sections of rats at 7 day after i.v. daily administering a single dose of 1 mL of saline and 1 mL of various Que formulations at 12 mg/kg. The scale bar is 200 μm and applies to all figure parts.CC BY · PubMed Central
Figure 5. The brain targeting of Exo-Que in vivo. (A) Representative fluorescence images of C57BL/6 mice brains treated with Que and Exo-Que via intravenous injection and peritoneal injection. (B) Representative fluorescent images of Que and Exo-Que (white arrows) at hippocampus of C57BL/6 mice after 24 h of i.p. administration of Que and Exo-Que. The scale bar is 100 μm and applies to all figure parts. (C) The content determination of Que in cerebrum and cerebellum of rats treated with single i.v. administration of Que and Exo-Que. The accumulation efficiency of Que was set as 100%. Data are expressed as means ± SD (n = 3), *p < 0.05, **p < 0.01.
Figure 5. The brain targeting of Exo-Que in vivo. (A) Representative fluorescence images of C57BL/6 mice brains treated with Que and Exo-Que via intravenous injection and peritoneal injection. (B) Representative fluorescent images of Que and Exo-Que (white arrows) at hippocampus of C57BL/6 mice after 24 h of i.p. administration of Que and Exo-Que. The scale bar is 100 μm and applies to all figure parts. (C) The content determination of Que in cerebrum and cerebellum of rats treated with single i.v. administration of Que and Exo-Que. The accumulation efficiency of Que was set as 100%. Data are expressed as means ± SD (n = 3), *p < 0.05, **p < 0.01.CC BY · PubMed Central
Figure 6. Exo-Que ameliorated the cognitive deficiency in OA-treated AD mice. (A) The platform crossing number in the spatial probe test. Data are expressed as mean ± SD (n = 3). * p < 0.05. (B) Relative time percentage spent on the target quadrant in a probe trial. Data are expressed as mean ± SD (n = 3). * p < 0.05. (C) Escape latencies analysis. Data are expressed as mean ± SD (n = 3). * p < 0.05, ** p < 0.01. (D) Representative path tracings of different groups.
Figure 6. Exo-Que ameliorated the cognitive deficiency in OA-treated AD mice. (A) The platform crossing number in the spatial probe test. Data are expressed as mean ± SD (n = 3). * p < 0.05. (B) Relative time percentage spent on the target quadrant in a probe trial. Data are expressed as mean ± SD (n = 3). * p < 0.05. (C) Escape latencies analysis. Data are expressed as mean ± SD (n = 3). * p < 0.05, ** p < 0.01. (D) Representative path tracings of different groups.CC BY · PubMed Central
Figure 7. (A) Representative immunofluorescence staining for neuron cell in CA1, CA3, and DG sector of the hippocampus via peritoneal injection of saline, Que and Exo-Que. Neun antibodies were used to stain neuron cells in hippocampus of brain. The scale bar is 250 μm and applies to all figure parts. Data are expressed as mean ± SD (n = 3). * p < 0.05, ** p < 0.01. (B) H&E staining of hippocampal sections treated with saline, Que and Exo-Que. Scale bar: 50 μm.
Figure 7. (A) Representative immunofluorescence staining for neuron cell in CA1, CA3, and DG sector of the hippocampus via peritoneal injection of saline, Que and Exo-Que. Neun antibodies were used to stain neuron cells in hippocampus of brain. The scale bar is 250 μm and applies to all figure parts. Data are expressed as mean ± SD (n = 3). * p < 0.05, ** p < 0.01. (B) H&E staining of hippocampal sections treated with saline, Que and Exo-Que. Scale bar: 50 μm.CC BY · PubMed Central
Figure 8. Neuroprotective role of naïve Exo on OA mice. (A) The platform crossing number in the spatial probe test. Data are expressed as mean ± SD (n = 3). *p < 0.05. (B) Relative time percentage spent on the target quadrant in a probe trial. Data are expressed as mean ± SD (n = 3). *p < 0.05. (C) Escape latencies analysis. Data are expressed as mean ± SD (n = 3). *p < 0.05. (D) Representative path tracings of different groups. (E) Representative immunofluorescence staining for neuron cell in CA1, CA3 and DG sector of the hippocampus via peritoneal injection of Exo. Neun antibodies were used to stain neuron cells in hippocampus of brain. The scale bar is 250 μm and applies to all figure parts. (F) H&E staining of hippocampal sections treated with Exo. Scale bar: 50 μm.
Figure 8. Neuroprotective role of naïve Exo on OA mice. (A) The platform crossing number in the spatial probe test. Data are expressed as mean ± SD (n = 3). *p < 0.05. (B) Relative time percentage spent on the target quadrant in a probe trial. Data are expressed as mean ± SD (n = 3). *p < 0.05. (C) Escape latencies analysis. Data are expressed as mean ± SD (n = 3). *p < 0.05. (D) Representative path tracings of different groups. (E) Representative immunofluorescence staining for neuron cell in CA1, CA3 and DG sector of the hippocampus via peritoneal injection of Exo. Neun antibodies were used to stain neuron cells in hippocampus of brain. The scale bar is 250 μm and applies to all figure parts. (F) H&E staining of hippocampal sections treated with Exo. Scale bar: 50 μm.CC BY · PubMed Central
Figure 9. Analysis of Exo-Que on neuroprotective effects in OA-induced AD mice through inhibiting CDK5-mediated phosphorylation of Tau and reducing formation of insoluble neurofibrillary tangles. (A) Western blot and quantitative analysis of the expression levels of CDK5 phosphor-CDK5 (pTyr15), Tau, phosphor-Tau (T231), cleaved caspase3 and cleaved caspase9 in sham, OA, OA + Que, OA + Exo and OA + Exo-Que groups. Data are expressed as mean ± SD (n = 3), * p < 0.05, ** p < 0.01. (B) The images of NFTs (blue arrows) on brain section in sham, OA, OA + Que, OA + Exo and OA + Exo-Que groups. Scale bar: 50 μm.
Figure 9. Analysis of Exo-Que on neuroprotective effects in OA-induced AD mice through inhibiting CDK5-mediated phosphorylation of Tau and reducing formation of insoluble neurofibrillary tangles. (A) Western blot and quantitative analysis of the expression levels of CDK5 phosphor-CDK5 (pTyr15), Tau, phosphor-Tau (T231), cleaved caspase3 and cleaved caspase9 in sham, OA, OA + Que, OA + Exo and OA + Exo-Que groups. Data are expressed as mean ± SD (n = 3), * p < 0.05, ** p < 0.01. (B) The images of NFTs (blue arrows) on brain section in sham, OA, OA + Que, OA + Exo and OA + Exo-Que groups. Scale bar: 50 μm.CC BY · PubMed Central

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Metadata

Authors
Qi, Y., Guo, L., Jiang, Y., Shi, Y., Sui, H., & Zhao, L.
Affiliations
Jinzhou Medical University (CN)
Corresponding author
Zhao, Liang
ORCID
Venue
Drug Delivery
Publisher
Informa UK Limited
Published
2020-01
Volume
27
Issue
1
Pages
745-755
ISSN
  • 1071-7544 (ISSN-L)
  • 1521-0464
DOI
10.1080/10717544.2020.1762262
PMC
PMC7269046
OpenAlex
W3025860373
Cited by
239
References
36
Citations by year
2026: 39 · 2025: 42 · 2024: 48 · 2023: 38 · 2022: 41 · 2021: 29 · 2020: 2
FWCI
16.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Drug Delivery (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Natural Science Foundation of Liaoning Province (-ZD-)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
Keywords
quercetin, exosomes, Alzheimer's disease, brain drug delivery, neurofibrillary tangles, tau phosphorylation, cyclin-dependent kinase 5, cognitive impairment, plasma exosomes, drug bioavailability, neuroprotection
MeSH terms
Alzheimer Disease, Animals, Biological Availability, Brain, Cognition, Drug Carriers, Mice, Inbred C57BL, Neurons, Phosphorylation, Quercetin, Neurofibrillary Tangles, Rats, Sprague-Dawley, Neuroprotective Agents, Maze Learning, Exosomes

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