Insulin resistance in the brains of individuals with Alzheimer’s disease (AD) has been hypothesised, but its existence, causes and consequences have not been established. Talbot et al. now provide evidence that dysregulated insulin signalling in the brain is a common and early event in AD. They measured insulin signalling pathway activation in post-mortem human brain samples (in which functional signalling is maintained for several hours after death), focusing on the cerebellar cortex (CC), which exhibits pathology in late-stage AD, and the hippo-campal formation (HF), which exhibits pathology in early-stage AD and is associated with cognitive decline. Compared with normal controls, activation of insulin signalling intermediates was lower in AD brains, especially in the HF. Insulin resistance was specifically associated with dysfunctional insulin receptor substrate 1 (IRS-1). The authors also identified two phosphorylated forms of IRS-1 (IRS-1pS616 and IRS-1pS636/639) as candidate biomarkers of brain insulin resistance and show that they are elevated in the HF of individuals with AD even without a history of diabetes. Finally, they show that both potential biomarkers are negatively correlated with cognitive function. These data strengthen the hypo thesis that brain insulin resistance contributes to the pathology of AD and indicate new avenues for prevention or therapy.
- Written by editorial staff. © 2012. Published by The Company of Biologists Ltd
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