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Oxidative stress-induced dysfunction of BVR-A promotes insulin resistance in Alzheimer disease

Recent research has revealed that insulin resistance is associated with a higher risk of developing Alzheimer's disease (AD). EU researchers have investigated the molecular pathways behind this discovery.
Oxidative stress-induced dysfunction of BVR-A promotes insulin resistance in Alzheimer disease
Post-mortem analysis of AD patients shows that brain insulin resistance is among the causes responsible for the observed cognitive decline. The BVRINSULINAD (Biliverdin reductase-A in brain insulin signalling and oxidative stress-mediated neurodegeneration) project has investigated the role of biliverdin reductase-A (BVR-A), a novel kinase involved in insulin signalling regulation.

BVR-A emerged as a unique Ser/Thr/Tyr kinase directly involved in the insulin signalling and representing an up-stream regulator of the insulin signalling cascade. BVRINSULINAD researchers have already demonstrated in previous research that oxidative/nitrosative stress (OS/NS)-induced impairment of BVR-A occurs in human AD brain.

Project partners analysed the age-dependent changes of BVR-A protein levels and activation, and total oxidative stress markers levels (PC, HNE, 3-NT). They also investigated investigated IR/IRS1 levels and activation in the brain of the triple transgenic mice model of AD (3xTg-AD). They then looked to see if these changes influence of amyloid beta (Abeta) levels and protein aggregation state.

Researchers also identified two phases in 3xTg mice: one (3-6 months) characterised by BVR-A inactivation and IRS-1 hyper-activation and the other (12-18 months) during which sustained BVR-A inactivation parallels IRS-1 inactivation and mTOR hyper-activation. Interestingly, these changes progress with increased OS/NS levels.

Similar alterations have been also found during the normal ageing process in WT mice with a normal genome (but only at a late stage), thus positing BVR-A impairment as a possible bridge in the transition from normal ageing to AD. It was noted that all these events precede TNF-α elevation, which is known to promote brain insulin resistance in AD.

To test the effects of insulin applied with a nasal spray to rekindle BVR-A activity, the researchers compared wild type and AD mice. The results are very encouraging and will be published shortly.

Care of AD patients is very costly, increasing dramatically in Europe and worldwide. BVRINSULINAD research results show that further research on the role of BVR-A impairment in this chronic disease promises to deliver a possible therapy and prevent insulin resistance.

Related information


Alzheimer's disease, oxidative stress, insulin resistance, BVRINSULINAD, biliverdin reductase-A
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