Humans with type 1 diabetes mellitus (DM) are subject to the development of diabetic leukoencephalopathy (DLE) with cognitive decline, brain atrophy, and white matter abnormalities. We examined advanced glycation end products (AGE) and upregulation of their receptor (RAGE) stimulated by persistent hyperglycemia as a causative pathway, intervening with RAGE blockade in a murine DLE model of type 1 (streptozotocin) DM. Over 8 months, DM mice received intraperitoneal injections of soluble RAGE or placebo alongside non-DM mice and RAGE−/− mice. Cognitive testing and magnetic resonance imaging (T2, magnetization transfer, diffusion tensor imaging), neuronal and oligodendroglial counts, synaptic and myelin measures, and RAGE–nuclear factor (NF)-κB pathway assessment was performed serially. DM mice developed cognitive deficits after 8 to 20 weeks of DM, oligodendroglial loss after 3 months, brain atrophy after 5 months, loss of synaptic machinery and fractional anisotropy at 8 months, and RAGE–NF-κB pathway activation. DM mice receiving soluble RAGE and RAGE−/− DM mice were protected from most of these abnormalities. Although DM led to NF-κB upregulation, NF-κB–mediated gene transcription was downregulated at 8 months, possibly due to later upregulation of transcription repressors B-cell lymphoma 3-encoded protein and NF-κB inhibitor Iκβζ. Blockade of RAGE has therapeutic importance in type 1 DM–mediated DLE within the complex regulation of NF-κB.
- Received March 14, 2012.
- Accepted July 9, 2012.
- © 2012 by the American Diabetes Association.
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