Altered expression of insulin-degrading enzyme and regulator of calcineurin in the rat intracerebral streptozotocin model and human apolipoprotein E-ε4–associated Alzheimer's disease

INTRODUCTION: This study assesses insulin-degrading enzyme (IDE) and regulator of calcineurin 1 (RCAN1) as potential mediators of brain insulin deficiency and neurodegeneration in experimental and human Alzheimer's disease (AD). METHODS: Temporal lobes from Long Evans rats treated with intracerebral streptozotocin or vehicle and postmortem frontal lobes from humans with normal aging AD (Braak 0-2), moderate (Braak 3-4) AD, or advanced (Braak 5-6) AD were used to measure IDE and RCAN mRNA and protein. RESULTS: Intracerebral streptozotocin significantly increased IDE and RCAN mRNA and protein. In humans with apolipoprotein E (ApoE) ε3/ε4 or ε4/ε4 and AD, IDE was elevated at Braak 3-4, but at Braak 5-6, IDE expression was significantly reduced. RCAN1 mRNA was similarly reduced in ApoE ε4+ patients with moderate or severe AD, whereas RCAN1 protein declined with the severity of AD and ApoE ε4 dose. DISCUSSION: The findings suggest that IDE and RCAN1 differentially modulate brain insulin signaling in relation to AD severity and ApoE genotype.