期刊
MOLECULAR NEUROBIOLOGY
卷 56, 期 4, 页码 2922-2943出版社
SPRINGER
DOI: 10.1007/s12035-018-1231-5
关键词
Alzheimer disease; Biliverdin reductase-A; Insulin resistance; Intranasal; Neuroprotection
资金
- Alzheimer's Association [NIRG-14-321307] Funding Source: Medline
- FP7 People: Marie-Curie Actions [624341] Funding Source: Medline
- Ministero dell'Istruzione, dell'Università e della Ricerca [20153NBRS3_003, RBSI144MT] Funding Source: Medline
- Banca d'Italia [12868/17] Funding Source: Medline
- Sapienza Università di Roma [C26H15JT9X] Funding Source: Medline
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 3xTg-AD mice by ameliorating BVR-A activation. These changes were associated with a reduction of nitrosative stress, Tau phosphorylation, and A 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.
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