Studies have shown similarities between the histopathological characteristics of NPC and Alzheimer's disease (AD) including amyloid and tau pathologies. While dysfunction in insulin signaling was widely detected in AD brain, the function of insulin signaling proteins has not been examined in NPC disease. In this study, we have examined the expression and phosphorylation of proteins linked to the insulin signaling pathway in the brain of 9 weeks old NPCnih mice. Our results showed lower expression of insulin receptor substrate 2 (IRS2) in the NPCnih mice, and insulin receptor substrate 1 (IRS1) expression was almost non-detectable in this NPC mouse model. This reduction was associated with the loss of expression for the regulatory p85 subunit of phosphatidylinositol 3-kinase (p85/PI3K). Interestingly, the impairment was observed to link to a greater reduction of Akt phosphorylation at residue T308 than 5473. This aberrant Akt phosphorylation could be contributing to lower GSK3 beta phosphorylation detected in the NPCnih mouse brain. To our knowledge, this is the first report documenting impaired insulin signaling in the brain of a NPC mouse model. (C) 2012 Elsevier Inc. All rights reserved.