Nanotechnology for microglial targeting and inhibition of neuroinflammation underlying Alzheimer’s pathology
Abstract Background Alzheimer's disease (AD) is considered to have a multifactorial etiology. The hallmark of AD is progressive neurodegeneration, which is characterized by the deepening loss of memory and a high mortality rate in the elderly. The neurodegeneration in AD is believed to be exace...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-01-01
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| Series: | Translational Neurodegeneration |
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| Online Access: | https://doi.org/10.1186/s40035-023-00393-7 |
| _version_ | 1797362953272426496 |
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| author | Hoda M. Gebril Aravind Aryasomayajula Mariana Reis Nogueira de Lima Kathryn E. Uhrich Prabhas V. Moghe |
| author_facet | Hoda M. Gebril Aravind Aryasomayajula Mariana Reis Nogueira de Lima Kathryn E. Uhrich Prabhas V. Moghe |
| author_sort | Hoda M. Gebril |
| collection | DOAJ |
| description | Abstract Background Alzheimer's disease (AD) is considered to have a multifactorial etiology. The hallmark of AD is progressive neurodegeneration, which is characterized by the deepening loss of memory and a high mortality rate in the elderly. The neurodegeneration in AD is believed to be exacerbated following the intercoupled cascades of extracellular amyloid beta (Aβ) plaques, uncontrolled microglial activation, and neuroinflammation. Current therapies for AD are mostly designed to target the symptoms, with limited ability to address the mechanistic triggers for the disease. In this study, we report a novel nanotechnology based on microglial scavenger receptor (SR)-targeting amphiphilic nanoparticles (NPs) for the convergent alleviation of fibril Aβ (fAβ) burden, microglial modulation, and neuroprotection. Methods We designed a nanotechnology approach to regulate the SR-mediated intracellular fAβ trafficking within microglia. We synthesized SR-targeting sugar-based amphiphilic macromolecules (AM) and used them as a bioactive shell to fabricate serum-stable AM–NPs via flash nanoprecipitation. Using electron microscopy, in vitro approaches, ELISA, and confocal microscopy, we investigated the effect of AM–NPs on Aβ fibrilization, fAβ-mediated microglial inflammation, and neurotoxicity in BV2 microglia and SH-SY5Y neuroblastoma cell lines. Results AM–NPs interrupted Aβ fibrilization, attenuated fAβ microglial internalization via targeting the fAβ-specific SRs, arrested the fAβ-mediated microglial activation and pro-inflammatory response, and accelerated lysosomal degradation of intracellular fAβ. Moreover, AM–NPs counteracted the microglial-mediated neurotoxicity after exposure to fAβ. Conclusions The AM–NP nanotechnology presents a multifactorial strategy to target pathological Aβ aggregation and arrest the fAβ-mediated pathological progression in microglia and neurons. Graphical Abstract |
| first_indexed | 2024-03-08T16:14:49Z |
| format | Article |
| id | doaj.art-e928cd5e312a460dbc51d678e149f4ad |
| institution | Directory Open Access Journal |
| issn | 2047-9158 |
| language | English |
| last_indexed | 2024-03-08T16:14:49Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Translational Neurodegeneration |
| spelling | doaj.art-e928cd5e312a460dbc51d678e149f4ad2024-01-07T12:41:51ZengBMCTranslational Neurodegeneration2047-91582024-01-0113112410.1186/s40035-023-00393-7Nanotechnology for microglial targeting and inhibition of neuroinflammation underlying Alzheimer’s pathologyHoda M. Gebril0Aravind Aryasomayajula1Mariana Reis Nogueira de Lima2Kathryn E. Uhrich3Prabhas V. Moghe4Department of Biomedical Engineering, Rutgers UniversityDepartment of Biomedical Engineering, Rutgers UniversityDepartment of Chemistry, University of CaliforniaDepartment of Chemistry, University of CaliforniaDepartment of Biomedical Engineering, Rutgers UniversityAbstract Background Alzheimer's disease (AD) is considered to have a multifactorial etiology. The hallmark of AD is progressive neurodegeneration, which is characterized by the deepening loss of memory and a high mortality rate in the elderly. The neurodegeneration in AD is believed to be exacerbated following the intercoupled cascades of extracellular amyloid beta (Aβ) plaques, uncontrolled microglial activation, and neuroinflammation. Current therapies for AD are mostly designed to target the symptoms, with limited ability to address the mechanistic triggers for the disease. In this study, we report a novel nanotechnology based on microglial scavenger receptor (SR)-targeting amphiphilic nanoparticles (NPs) for the convergent alleviation of fibril Aβ (fAβ) burden, microglial modulation, and neuroprotection. Methods We designed a nanotechnology approach to regulate the SR-mediated intracellular fAβ trafficking within microglia. We synthesized SR-targeting sugar-based amphiphilic macromolecules (AM) and used them as a bioactive shell to fabricate serum-stable AM–NPs via flash nanoprecipitation. Using electron microscopy, in vitro approaches, ELISA, and confocal microscopy, we investigated the effect of AM–NPs on Aβ fibrilization, fAβ-mediated microglial inflammation, and neurotoxicity in BV2 microglia and SH-SY5Y neuroblastoma cell lines. Results AM–NPs interrupted Aβ fibrilization, attenuated fAβ microglial internalization via targeting the fAβ-specific SRs, arrested the fAβ-mediated microglial activation and pro-inflammatory response, and accelerated lysosomal degradation of intracellular fAβ. Moreover, AM–NPs counteracted the microglial-mediated neurotoxicity after exposure to fAβ. Conclusions The AM–NP nanotechnology presents a multifactorial strategy to target pathological Aβ aggregation and arrest the fAβ-mediated pathological progression in microglia and neurons. Graphical Abstracthttps://doi.org/10.1186/s40035-023-00393-7Amphiphilic nanoparticleMicrogliaFibril amyloid betaAlzheimer’s diseaseNeuroinflammationScavenger receptor |
| spellingShingle | Hoda M. Gebril Aravind Aryasomayajula Mariana Reis Nogueira de Lima Kathryn E. Uhrich Prabhas V. Moghe Nanotechnology for microglial targeting and inhibition of neuroinflammation underlying Alzheimer’s pathology Translational Neurodegeneration Amphiphilic nanoparticle Microglia Fibril amyloid beta Alzheimer’s disease Neuroinflammation Scavenger receptor |
| title | Nanotechnology for microglial targeting and inhibition of neuroinflammation underlying Alzheimer’s pathology |
| title_full | Nanotechnology for microglial targeting and inhibition of neuroinflammation underlying Alzheimer’s pathology |
| title_fullStr | Nanotechnology for microglial targeting and inhibition of neuroinflammation underlying Alzheimer’s pathology |
| title_full_unstemmed | Nanotechnology for microglial targeting and inhibition of neuroinflammation underlying Alzheimer’s pathology |
| title_short | Nanotechnology for microglial targeting and inhibition of neuroinflammation underlying Alzheimer’s pathology |
| title_sort | nanotechnology for microglial targeting and inhibition of neuroinflammation underlying alzheimer s pathology |
| topic | Amphiphilic nanoparticle Microglia Fibril amyloid beta Alzheimer’s disease Neuroinflammation Scavenger receptor |
| url | https://doi.org/10.1186/s40035-023-00393-7 |
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