Impairment of biliverdin reductase-A (BVR-A) is an early event leading to brain insulin resistance in AD. Intranasal insulin (INI) administration is under evaluation as a strategy to alleviate brain insulin resistance; however, the molecular mechanisms underlying INI beneficial effects are still unclear. We show that INI improves insulin signaling activation in the hippocampus and cortex of adult and aged 3×Tg-AD mice by ameliorating BVR-A activation. These changes were associated with a reduction of nitrosative stress, Tau phosphorylation, and Aβ oligomers in brain, along with improved cognitive functions. The role of BVR-A was strengthened by showing that cells lacking BVR-A: (i) develop insulin resistance if treated with insulin and (ii) can be recovered from insulin resistance only if treated with a BVR-A-mimetic peptide. These novel findings shed light on the mechanisms underlying INI treatment effects and suggest BVR-A as potential therapeutic target to prevent brain insulin resistance in AD.

Barone, E., Tramutola, A., Triani, F., Calcagnini, S., Di Domenico, F., Ripoli, C., Gaetani, S., Grassi, C., Butterfield, A. D., Cassano, T., Perluigi, M., Biliverdin reductase-A mediates the beneficial effects of intranasal insulin in Alzheimer disease., <<MOLECULAR NEUROBIOLOGY>>, 2019; 56 (4): 2922-2943. [doi:10.1007/s12035-018-1231-5] [http://hdl.handle.net/10807/128705]

Biliverdin reductase-A mediates the beneficial effects of intranasal insulin in Alzheimer disease.

Ripoli, C.;Grassi, C.;
2019

Abstract

Impairment of biliverdin reductase-A (BVR-A) is an early event leading to brain insulin resistance in AD. Intranasal insulin (INI) administration is under evaluation as a strategy to alleviate brain insulin resistance; however, the molecular mechanisms underlying INI beneficial effects are still unclear. We show that INI improves insulin signaling activation in the hippocampus and cortex of adult and aged 3×Tg-AD mice by ameliorating BVR-A activation. These changes were associated with a reduction of nitrosative stress, Tau phosphorylation, and Aβ oligomers in brain, along with improved cognitive functions. The role of BVR-A was strengthened by showing that cells lacking BVR-A: (i) develop insulin resistance if treated with insulin and (ii) can be recovered from insulin resistance only if treated with a BVR-A-mimetic peptide. These novel findings shed light on the mechanisms underlying INI treatment effects and suggest BVR-A as potential therapeutic target to prevent brain insulin resistance in AD.
Inglese
Barone, E., Tramutola, A., Triani, F., Calcagnini, S., Di Domenico, F., Ripoli, C., Gaetani, S., Grassi, C., Butterfield, A. D., Cassano, T., Perluigi, M., Biliverdin reductase-A mediates the beneficial effects of intranasal insulin in Alzheimer disease., <<MOLECULAR NEUROBIOLOGY>>, 2019; 56 (4): 2922-2943. [doi:10.1007/s12035-018-1231-5] [http://hdl.handle.net/10807/128705]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/128705
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