As impaired insulin signalling (IIS) is a risk factor for Alzheimer's disease we crossed mice (Tg2576) overexpressing human amyloid precursor protein (APP), with insulin receptor substrate 2 null (Irs2(-/-)) mice which develop insulin resistance. The resulting Tg2576/Irs2(-/-) animals had increased tau phosphorylation but a paradoxical amelioration of A beta pathology. An increase of the A beta binding protein transthyretin suggests that increased clearance of A beta underlies the reduction in plaques. Increased tau phosphorylation correlated with reduced tau-phosphatase PP2A, despite an inhibition of the tau-kinase glycogen synthase kinase-3. Our findings demonstrate that disruption of IIS in Tg2576 mice has divergent effects on pathological processes-a reduction in aggregated A beta but an increase in tau phosphorylation. However, as these effects are accompanied by improvement in behavioural deficits, our findings suggest a novel protective effect of disrupting IRS2 signalling in AD which may be a useful therapeutic strategy for this condition. (C) 2009 Elsevier Inc. All rights reserved.