Intranasally Administered EVs from hiPSC-derived NSCs Alter the Transcriptomic Profile of Activated Microglia and Conserve Brain Function in an Alzheimer's Model

Madhu, L. N.; Kodali, M.; Upadhya, R.; Rao, S.; Shuai, B.; Somayaji, Y.; Attaluri, S.; Kirmani, M.; Gupta, S.; Maness, N.; Rao, X.; Cai, J.; Shetty, A.

doi:10.1101/2024.01.18.576313

bioRxiv · 10.1101/2024.01.18.576313

Intranasally Administered EVs from hiPSC-derived NSCs Alter the Transcriptomic Profile of Activated Microglia and Conserve Brain Function in an Alzheimer's Model

Madhu, L. N.·Kodali, M.·Upadhya, R.·Rao, S.·Shuai, B.·Somayaji, Y.·Attaluri, S.·Kirmani, M.·Gupta, S.·Maness, N.·Rao, X.·Cai, J.·Shetty, A.

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Abstract

Antiinflammatory extracellular vesicles (EVs) derived from human induced pluripotent stem cell (hiPSC)-derived neural stem cells (NSCs) hold promise as a disease-modifying biologic for Alzheimers disease (AD). This study directly addressed this issue by examining the effects of intranasal administrations of hiPSC-NSC-EVs to 3-month-old 5xFAD mice. The EVs were internalized by all microglia, which led to reduced expression of multiple genes associated with disease-associated microglia, inflammasome, and interferon-1 signaling. Furthermore, the effects of hiPSC-NSC-EVs persisted for two months post-treatment in the hippocampus, evident from reduced microglial clusters, inflammasome complexes, and expression of proteins and/or genes linked to the activation of inflammasomes, p38/mitogen-activated protein kinase, and interferon-1 signaling. The amyloid-beta (A{beta}) plaques, A{beta}-42, and phosphorylated-tau concentrations were also diminished, leading to better cognitive and mood function in 5xFAD mice. Thus, early intervention with hiPSC-NSC-EVs in AD may help maintain better brain function by restraining the progression of adverse neuroinflammatory signaling cascades.

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Madhu, L. N., Kodali, M., Upadhya, R., Rao, S., Shuai, B., Somayaji, Y., Attaluri, S., Kirmani, M., Gupta, S., Maness, N., Rao, X., Cai, J., Shetty, A.. 2024-01-20. Intranasally Administered EVs from hiPSC-derived NSCs Alter the Transcriptomic Profile of Activated Microglia and Conserve Brain Function in an Alzheimer's Model. https://doi.org/10.1101/2024.01.18.576313

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