A Role For Astrocytic Insulin-Like Growth Factor I Receptors In The Response To Ischemic Insult

Suda, K.; Pignatelli, J.; Genis, L.; Fernandez, A. M.; Fernandez de Sevilla, M. E.; Fernandez de la Cruz, I.; Pozo-Rodrigalvarez, A.; de Ceballos, M. L.; Diaz-Pacheco, S.; Herrero-Labrador, R.; Torres Aleman, I.

doi:10.1101/2023.01.13.523904

bioRxiv · 10.1101/2023.01.13.523904

A Role For Astrocytic Insulin-Like Growth Factor I Receptors In The Response To Ischemic Insult

Suda, K.·Pignatelli, J.·Genis, L.·Fernandez, A. M.·Fernandez de Sevilla, M. E.·Fernandez de la Cruz, I.·Pozo-Rodrigalvarez, A.·de Ceballos, M. L.·Diaz-Pacheco, S.·Herrero-Labrador, R.·Torres Aleman, I.

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Abstract

Increased neurotrophic support, including insulin-like growth factor I (IGF-I), is an important aspect of the adaptive response to ischemic insult. However, recent findings indicate that the IGF-I receptor (IGF-IR) in neurons plays a detrimental role in the response to stroke. Thus, we investigated the role of astrocytic IGF-IR on ischemic insults by deleting it using tamoxifen-regulated Cre deletion in glial fibrillary acidic protein (GFAP) astrocytes, a major cellular component in the response to injury. Ablation of IGF-IR in astrocytes (GFAP-IGF-IR KO mice) resulted in larger ischemic lesions, greater blood-brain-barrier disruption and more deteriorated sensorimotor coordination. RNAseq detetected increases in inflammatory, cell adhesion and angiogenic pathways, while the expression of various classical biomarkers of response to ischemic lesion, including aquaporin 4, complement 1q subunit a, early growth response protein 1, and C-C motif chemokine ligand 2, were significantly increased at the lesion site compared to control littermates. While serum IGF-I levels after injury were decreased in both control and GFAP-IR KO mice, brain IGF-I mRNA expression show larger increases in the latter. Further, greater damage was also accompanied by altered glial reactivity as reflected by changes in the morphology of GFAP astrocytes, and relative abundance of ionized calcium binding adaptor molecule 1 microglia. These results suggest a protective role for astrocytic IGF-IR in the response to ischemic injury.

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Suda, K., Pignatelli, J., Genis, L., Fernandez, A. M., Fernandez de Sevilla, M. E., Fernandez de la Cruz, I., Pozo-Rodrigalvarez, A., de Ceballos, M. L., Diaz-Pacheco, S., Herrero-Labrador, R., Torres Aleman, I.. 2023-01-13. A Role For Astrocytic Insulin-Like Growth Factor I Receptors In The Response To Ischemic Insult. https://doi.org/10.1101/2023.01.13.523904

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