TI - Deletion of Irs2 reduces amyloid deposition and rescues behavioural deficits in APP transgenic mice . AB - Abstract As impaired insulin signalling ( IIS ) is a risk factor for Alzheimer's disease we crossed mice ( Tg2576 ) over-expressing 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 Abeta pathology . An increase of the Abeta binding protein transthyretin suggests that increased clearance of Abeta 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 Abeta 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 .