Deposition of amyloid-β peptide (Aβ) in the brain of diabetes is poorly understood. The receptor for advanced glycation end products (RAGE) at the blood-brain barrier (BBB) is critical for regulation of Aβ homeostasis in the brain. In this studies, we used streptozotocin-induced diabetic mice to observe the expression of RAGE at the BBB by Western blot and immunocytochemical analysis, and the in vivo blood-to-brain influx transport of 125I-Aβ1-40 using the permeability surface area product (PS) and brain capillary uptake. In the diabetic mice with hyperglycemia (>16.0 mmol/L) at 6 weeks, RAGE expression at the BBB was significantly upregulated, no significant changes of RAGE levels were found at 1 and 3 weeks after diabetes induction. The data of PS and brain capillary uptake for Aβ showed significant RAGE-dependent transport of Aβ across the BBB and substantial RAGE-dependent brain capillary uptake at 6 weeks after diabetes induction. We conclude that the upregulation of RAGE at the BBB contributes to cerebral Aβ deposition in the diabetes. Synapse 63:636-642, 2009. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]