TY - JOUR
T1 - Biliverdin Reductase-A Mediates the Beneficial Effects of Intranasal Insulin in Alzheimer Disease
AU - Barone, Eugenio
AU - Tramutola, Antonella
AU - Triani, Francesca
AU - Calcagnini, Silvio
AU - Di Domenico, Fabio
AU - Ripoli, Cristian
AU - Gaetani, Silvana
AU - Grassi, Claudio
AU - Butterfield, D. Allan
AU - Cassano, Tommaso
AU - Perluigi, Marzia
N1 - Publisher Copyright:
© 2019, Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2019/4/1
Y1 - 2019/4/1
N2 - 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.
AB - 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.
KW - Alzheimer disease
KW - Biliverdin reductase-A
KW - Insulin resistance
KW - Intranasal
KW - Neuroprotection
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UR - http://www.scopus.com/inward/citedby.url?scp=85051645596&partnerID=8YFLogxK
U2 - 10.1007/s12035-018-1231-5
DO - 10.1007/s12035-018-1231-5
M3 - Article
C2 - 30073505
AN - SCOPUS:85051645596
SN - 0893-7648
VL - 56
SP - 2922
EP - 2943
JO - Molecular Neurobiology
JF - Molecular Neurobiology
IS - 4
ER -