Diabetes, leukoencephalopathy and rage.
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.
Toth
Cory
C
Department of Clinical Neurosciences and the Neuroscience Research Group, University of Calgary, Alberta, Canada. corytoth@shaw.ca
Schmidt
Ann Marie
AM
Tuor
Ursula I
UI
Francis
George
G
Foniok
Tadeusz
T
Brussee
Valentine
V
Kaur
Jaspreet
J
Yan
Shi Fang
SF
Martinez
Jose A
JA
Barber
Philip A
PA
Buchan
Alastair
A
Zochodne
Douglas W
DW
D000818:Animals; D001921:Brain / Q000473:pathology*; D017931:DNA Primers; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004660:Encephalitis / Q000473:pathology*; D017127:Glycation End Products, Advanced; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D015345:Oligonucleotide Probes; D016133:Polymerase Chain Reaction; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*
D017931:DNA Primers; D017127:Glycation End Products, Advanced; D015345:Oligonucleotide Probes; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic