Extracellular vesicles from human‐induced pluripotent stem cell‐derived neural stem cells alleviate proinflammatory cascades within disease‐associated microglia in Alzheimer's disease
Abstract As current treatments for Alzheimer's disease (AD) lack disease‐modifying interventions, novel therapies capable of restraining AD progression and maintaining better brain function have great significance. Anti‐inflammatory extracellular vesicles (EVs) derived from human induced plurip...
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Wiley
2024-11-01
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| Series: | Journal of Extracellular Vesicles |
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| Online Access: | https://doi.org/10.1002/jev2.12519 |
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| author | Leelavathi N. Madhu Maheedhar Kodali Raghavendra Upadhya Shama Rao Yogish Somayaji Sahithi Attaluri Bing Shuai Maha Kirmani Shreyan Gupta Nathaniel Maness Xiaolan Rao James J. Cai Ashok K. Shetty |
| author_facet | Leelavathi N. Madhu Maheedhar Kodali Raghavendra Upadhya Shama Rao Yogish Somayaji Sahithi Attaluri Bing Shuai Maha Kirmani Shreyan Gupta Nathaniel Maness Xiaolan Rao James J. Cai Ashok K. Shetty |
| author_sort | Leelavathi N. Madhu |
| collection | DOAJ |
| description | Abstract As current treatments for Alzheimer's disease (AD) lack disease‐modifying interventions, novel therapies capable of restraining AD progression and maintaining better brain function have great significance. Anti‐inflammatory extracellular vesicles (EVs) derived from human induced pluripotent stem cell (hiPSC)‐derived neural stem cells (NSCs) hold promise as a disease‐modifying biologic for AD. This study directly addressed this issue by examining the effects of intranasal (IN) administrations of hiPSC‐NSC‐EVs in 3‐month‐old 5xFAD mice. IN administered hiPSC‐NSC‐EVs incorporated into microglia, including plaque‐associated microglia, and encountered astrocyte soma and processes in the brain. Single‐cell RNA sequencing revealed transcriptomic changes indicative of diminished activation of microglia and astrocytes. Multiple genes linked to disease‐associated microglia, NOD‐, LRR‐, and pyrin domain‐containing protein 3 (NLRP3)‐inflammasome and interferon‐1 (IFN‐1) signalling displayed reduced expression in microglia. Adding hiPSC‐NSC‐EVs to cultured human microglia challenged with amyloid‐beta oligomers resulted in similar effects. Astrocytes also displayed reduced expression of genes linked to IFN‐1 and interleukin‐6 signalling. Furthermore, the modulatory effects of hiPSC‐NSC‐EVs on microglia in the hippocampus persisted 2 months post‐EV treatment without impacting their phagocytosis function. Such effects were evidenced by reductions in microglial clusters and inflammasome complexes, concentrations of mediators, and end products of NLRP3 inflammasome activation, the expression of genes and/or proteins involved in the activation of p38/mitogen‐activated protein kinase and IFN‐1 signalling, and unaltered phagocytosis function. The extent of astrocyte hypertrophy, amyloid‐beta plaques, and p‐tau were also reduced in the hippocampus. Such modulatory effects of hiPSC‐NSC‐EVs also led to better cognitive and mood function. Thus, early hiPSC‐NSC‐EV intervention in AD can maintain better brain function by reducing adverse neuroinflammatory signalling cascades, amyloid‐beta plaque load, and p‐tau. These results reflect the first demonstration of the efficacy of hiPSC‐NSC‐EVs to restrain neuroinflammatory signalling cascades in an AD model by inducing transcriptomic changes in activated microglia and reactive astrocytes. |
| format | Article |
| id | doaj-art-9df2a85d0a5b4413812051a65eeed0dd |
| institution | OA Journals |
| issn | 2001-3078 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Wiley |
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| series | Journal of Extracellular Vesicles |
| spelling | doaj-art-9df2a85d0a5b4413812051a65eeed0dd2025-08-20T02:07:09ZengWileyJournal of Extracellular Vesicles2001-30782024-11-011311n/an/a10.1002/jev2.12519Extracellular vesicles from human‐induced pluripotent stem cell‐derived neural stem cells alleviate proinflammatory cascades within disease‐associated microglia in Alzheimer's diseaseLeelavathi N. Madhu0Maheedhar Kodali1Raghavendra Upadhya2Shama Rao3Yogish Somayaji4Sahithi Attaluri5Bing Shuai6Maha Kirmani7Shreyan Gupta8Nathaniel Maness9Xiaolan Rao10James J. Cai11Ashok K. Shetty12Institute for Regenerative Medicine, Department of Cell Biology and Genetics, College of Medicine Texas A&M University Health Science Center, College Station Texas USAInstitute for Regenerative Medicine, Department of Cell Biology and Genetics, College of Medicine Texas A&M University Health Science Center, College Station Texas USAInstitute for Regenerative Medicine, Department of Cell Biology and Genetics, College of Medicine Texas A&M University Health Science Center, College Station Texas USAInstitute for Regenerative Medicine, Department of Cell Biology and Genetics, College of Medicine Texas A&M University Health Science Center, College Station Texas USAInstitute for Regenerative Medicine, Department of Cell Biology and Genetics, College of Medicine Texas A&M University Health Science Center, College Station Texas USAInstitute for Regenerative Medicine, Department of Cell Biology and Genetics, College of Medicine Texas A&M University Health Science Center, College Station Texas USAInstitute for Regenerative Medicine, Department of Cell Biology and Genetics, College of Medicine Texas A&M University Health Science Center, College Station Texas USAInstitute for Regenerative Medicine, Department of Cell Biology and Genetics, College of Medicine Texas A&M University Health Science Center, College Station Texas USADepartment of Veterinary Integrative Biosciences Texas A&M College of Veterinary Medicine, College Station Texas USAInstitute for Regenerative Medicine, Department of Cell Biology and Genetics, College of Medicine Texas A&M University Health Science Center, College Station Texas USAInstitute for Regenerative Medicine, Department of Cell Biology and Genetics, College of Medicine Texas A&M University Health Science Center, College Station Texas USADepartment of Veterinary Integrative Biosciences Texas A&M College of Veterinary Medicine, College Station Texas USAInstitute for Regenerative Medicine, Department of Cell Biology and Genetics, College of Medicine Texas A&M University Health Science Center, College Station Texas USAAbstract As current treatments for Alzheimer's disease (AD) lack disease‐modifying interventions, novel therapies capable of restraining AD progression and maintaining better brain function have great significance. Anti‐inflammatory extracellular vesicles (EVs) derived from human induced pluripotent stem cell (hiPSC)‐derived neural stem cells (NSCs) hold promise as a disease‐modifying biologic for AD. This study directly addressed this issue by examining the effects of intranasal (IN) administrations of hiPSC‐NSC‐EVs in 3‐month‐old 5xFAD mice. IN administered hiPSC‐NSC‐EVs incorporated into microglia, including plaque‐associated microglia, and encountered astrocyte soma and processes in the brain. Single‐cell RNA sequencing revealed transcriptomic changes indicative of diminished activation of microglia and astrocytes. Multiple genes linked to disease‐associated microglia, NOD‐, LRR‐, and pyrin domain‐containing protein 3 (NLRP3)‐inflammasome and interferon‐1 (IFN‐1) signalling displayed reduced expression in microglia. Adding hiPSC‐NSC‐EVs to cultured human microglia challenged with amyloid‐beta oligomers resulted in similar effects. Astrocytes also displayed reduced expression of genes linked to IFN‐1 and interleukin‐6 signalling. Furthermore, the modulatory effects of hiPSC‐NSC‐EVs on microglia in the hippocampus persisted 2 months post‐EV treatment without impacting their phagocytosis function. Such effects were evidenced by reductions in microglial clusters and inflammasome complexes, concentrations of mediators, and end products of NLRP3 inflammasome activation, the expression of genes and/or proteins involved in the activation of p38/mitogen‐activated protein kinase and IFN‐1 signalling, and unaltered phagocytosis function. The extent of astrocyte hypertrophy, amyloid‐beta plaques, and p‐tau were also reduced in the hippocampus. Such modulatory effects of hiPSC‐NSC‐EVs also led to better cognitive and mood function. Thus, early hiPSC‐NSC‐EV intervention in AD can maintain better brain function by reducing adverse neuroinflammatory signalling cascades, amyloid‐beta plaque load, and p‐tau. These results reflect the first demonstration of the efficacy of hiPSC‐NSC‐EVs to restrain neuroinflammatory signalling cascades in an AD model by inducing transcriptomic changes in activated microglia and reactive astrocytes.https://doi.org/10.1002/jev2.12519Anti‐inflammatory effectsdisease‐associated microgliaextracellular vesicleshuman induced pluripotent stem cell‐derived neural stem cellsinflammasomesinterferon 1 signalling |
| spellingShingle | Leelavathi N. Madhu Maheedhar Kodali Raghavendra Upadhya Shama Rao Yogish Somayaji Sahithi Attaluri Bing Shuai Maha Kirmani Shreyan Gupta Nathaniel Maness Xiaolan Rao James J. Cai Ashok K. Shetty Extracellular vesicles from human‐induced pluripotent stem cell‐derived neural stem cells alleviate proinflammatory cascades within disease‐associated microglia in Alzheimer's disease Journal of Extracellular Vesicles Anti‐inflammatory effects disease‐associated microglia extracellular vesicles human induced pluripotent stem cell‐derived neural stem cells inflammasomes interferon 1 signalling |
| title | Extracellular vesicles from human‐induced pluripotent stem cell‐derived neural stem cells alleviate proinflammatory cascades within disease‐associated microglia in Alzheimer's disease |
| title_full | Extracellular vesicles from human‐induced pluripotent stem cell‐derived neural stem cells alleviate proinflammatory cascades within disease‐associated microglia in Alzheimer's disease |
| title_fullStr | Extracellular vesicles from human‐induced pluripotent stem cell‐derived neural stem cells alleviate proinflammatory cascades within disease‐associated microglia in Alzheimer's disease |
| title_full_unstemmed | Extracellular vesicles from human‐induced pluripotent stem cell‐derived neural stem cells alleviate proinflammatory cascades within disease‐associated microglia in Alzheimer's disease |
| title_short | Extracellular vesicles from human‐induced pluripotent stem cell‐derived neural stem cells alleviate proinflammatory cascades within disease‐associated microglia in Alzheimer's disease |
| title_sort | extracellular vesicles from human induced pluripotent stem cell derived neural stem cells alleviate proinflammatory cascades within disease associated microglia in alzheimer s disease |
| topic | Anti‐inflammatory effects disease‐associated microglia extracellular vesicles human induced pluripotent stem cell‐derived neural stem cells inflammasomes interferon 1 signalling |
| url | https://doi.org/10.1002/jev2.12519 |
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