Deletion of calcineurin from astrocytes reproduces proteome signature of Alzheimer's disease and epilepsy and predisposes to seizures

Tapella, L.; Dematteis, G.; Ruffinatti, F. A.; Ponzoni, L.; Fiordaliso, F.; Corbelli, A.; Albanese, E.; Pistolato, B.; Pagano, J.; Barberis, E.; Marengo, E.; Balducci, C.; Forloni, G.; Verpelli, C.; Sala, C.; Distasi, C.; Sala, M.; Genazani, A. A.; Manfredi, M.; Lim, D.

doi:10.1101/2020.03.21.001321

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bioRxiv · 10.1101/2020.03.21.001321

Deletion of calcineurin from astrocytes reproduces proteome signature of Alzheimer's disease and epilepsy and predisposes to seizures

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Abstract

In astrocytes, calcineurin (CaN) is involved in neuroinflammation and gliosis, while its role in healthy CNS or in early neuro-pathogenesis is poorly understood. Here we report that in astroglial CaN KO (ACN-KO) mice, at one month of age, proteome is deranged in hippocampus and cerebellum. Bioinformatic analysis reveals association with Alzheimers disease (AD) and epilepsy. We found significant overlap with the proteome of an AD mouse model and of human subjects with drug-resistant epilepsy. In Barnes maze ACN-KO mice learned the task but adopted serial search strategy. Strikingly, from five months of age ACN-KO mice develop spontaneous seizures with an inflammatory signature of epileptic brains. These results suggest that astroglial CaN KO impairs hippocampal connectivity, produces proteome features of neurological disorders and predisposes mice to seizures. We suggest that astroglial CaN may serve as a novel Ca2+-sensitive switch which regulates protein expression and homeostasis in the CNS.

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Tapella, L., Dematteis, G., Ruffinatti, F. A., Ponzoni, L., Fiordaliso, F., Corbelli, A., Albanese, E., Pistolato, B., Pagano, J., Barberis, E., Marengo, E., Balducci, C., Forloni, G., Verpelli, C., Sala, C., Distasi, C., Sala, M., Genazani, A. A., Manfredi, M., Lim, D.. 2020-03-23. Deletion of calcineurin from astrocytes reproduces proteome signature of Alzheimer's disease and epilepsy and predisposes to seizures. https://doi.org/10.1101/2020.03.21.001321

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