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Longstanding diabetes mellitus damages kidney, retina, peripheral nerve and blood vessels, but brain is not usually considered a primary target. We describe direct involvement of the brain, particularly white matter, in long-term (9 months) experimental diabetes of mice, not previously modeled, correlating magnetic resonance (MR) imaging with quantitative histological assessment. Leukoencephalopathy and cerebral atrophy, resembling that encountered in diabetic humans, developed in diabetic mice and was accompanied by time-related development of cognitive changes in behavioural testing. Increased RAGE (receptor for advanced glycation end products) expression, a mediator of widespread diabetic complications, increased dramatically at sites of white matter damage in regions of myelination. RAGE expression was also elevated within neurons, astrocytes and microglia in grey matter and within oligodendrocytes in white matter. RAGE null diabetic mice had significantly less neurodegenerative changes when compared to wild-type diabetic mice. Our findings identify a robust and novel model of cerebral, particularly white matter, involvement with diabetes associated with abnormal RAGE signaling.

Original publication

DOI

10.1016/j.nbd.2006.03.015

Type

Journal article

Journal

Neurobiol Dis

Publication Date

08/2006

Volume

23

Pages

445 - 461

Keywords

Advanced Glycosylation End Product-Specific Receptor, Animals, Brain, DNA Primers, Diabetes Mellitus, Experimental, Encephalitis, Glycosylation End Products, Advanced, Magnetic Resonance Imaging, Male, Mice, Oligonucleotide Probes, Polymerase Chain Reaction, Receptors, Immunologic