N epsilon-carboxymethyllysine in brain aging, diabetes mellitus, and Alzheimer's disease.
Oxidative stress has been implicated in the pathophysiology of Alzheimer's disease (AD) and diabetes mellitus (DM). N epsilon-carboxymethyllysine (CML) is an advanced glycation end product (AGE) recently found to be associated with oxidative stress mechanisms. Using immunocytochemical methods we examined the distribution of CML in brain tissue from AD and DM subjects and aging controls. CML reactivity was present in the cytoplasm of neurons, but there were marked differences in the intensity of expression, number of cells, and topographical distribution. CML expression was higher in hippocampus than in frontal and temporal cortex. In the hippocampus, neuronal and, to an extent, glial expression was more marked in CA3 and CA4 than in CA1 and CA2. In AD, CML was found to be coexpressed with tau protein, showing the similar neurofibrillary tangle shape, as well as in neuritic plaques but not in the core of amyloid plaques. We noted an increasing degree of CML expression such that the highest reactivity was evident in those with both AD and DM, followed by AD, DM, and aging controls. There was an inverse relationship between Braak staging and topography of CML expression. Although DM cases did not show Abeta deposition or neurofibrillary tangles, these findings suggest increased CML expression is not limited to AD. Nonetheless, high CML expression in AD with coexistent DM suggests there are additive effects compared with AD alone. It is plausible that the microangiopathy also associated with DM could worsen AD pathogenesis.
Gironès
Xavier
X
Institute of Neurological Sciences, International University of Catalonia, Barcelona, Spain.
Guimerà
Arantxa
A
Cruz-Sánchez
Celia-Z
CZ
Ortega
Arantxa
A
Sasaki
Noboyuki
N
Makita
Zenji
Z
Lafuente
José Vivente
JV
Kalaria
Raj
R
Cruz-Sánchez
Félix F
FF
D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000187:drug effects*; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000187:drug effects*; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism* / Q000473:pathology; D005260:Female; D017127:Glycation End Products, Advanced; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D058225:Plaque, Amyloid / Q000187:drug effects; D016875:tau Proteins / Q000378:metabolism
D017127:Glycation End Products, Advanced; D016875:tau Proteins; C048496:N(6)-carboxymethyllysine; D008239:Lysine