as therapeutic strategy to alleviate b.i.r. in AD. However, the exact molecular mechanisms underlying I-Ins beneficial effects are still unclear. The goal of our project was to clarify whether the I-Insassociated beneficial effects were mediated by the restoration of BVR-A activity. Methods:Changes of (1) the insulin signaling machinery (IR/IRS1/ ERK1/2/AKT/mTOR levels and activation) (2) total OS markers (PC, HNE, 3-NT) and (3) Ab and tau levels, were evaluated in the hippocampus and cortex of 3xTg-AD and WT mice undergoing an early (4 months) or late (10 moths) I-Ins treatment (1 U/day, 3 times per week, for 2 months) (Fig.2). The morris water maze (MWM) and the novel object recognition (NOR) tasks were used to test cognitive functions. Cell-based experiments to support in vivo data were performed in HEK-APPSwe cells. Results:I-Ins administration rescues the activation of BVR-A both in young and old 3xTg-AD mice. Improved BVR-A activity is associated with (1) a restoration of the insulin signaling cascade, (2) reduced OS markers and (3) a reduction of Tau pathology. All these changes parallel an improved cognition (Fig.3). Cell-based experiments confirmed the central role of BVR-A by showing that the effects of insulin are abolished when BVR-A is knocked-down. Conclusions:Our data highlight that BVR-A plays a pivotal role in the regulation of the insulin signaling in the brain. Restoration of BVR-A activity first, sheds light on the molecular mechanisms underlie I-Ins-mediated beneficial effects, and then suggest the role of BVR-A as potential therapeutic target to prevent b.i.r.in AD.