Immunohistochemical analysis of human brain suggests pathological synergism of Alzheimer's disease and diabetes mellitus.
It has been extensively reported that diabetes mellitus (DM) patients have a higher risk of developing Alzheimer's disease (AD), but a mechanistic connection between both pathologies has not been provided so far. Carbohydrate-derived advanced glycation endproducts (AGEs) have been implicated in the chronic complications of DM and have been reported to play an important role in the pathogenesis of AD. The earliest histopathological manifestation of AD is the apparition of extracellular aggregates of the amyloid beta peptide (Abeta). To investigate possible correlations between AGEs and Abeta aggregates with both pathologies, we have performed an immuhistochemical study in human post-mortem samples of AD, AD with diabetes (ADD), diabetic and nondemented controls. ADD brains showed increased number of Abeta dense plaques and receptor for AGEs (RAGE)-positive and Tau-positive cells, higher AGEs levels and major microglial activation, compared to AD brain. Our results indicate that ADD patients present a significant increase of cell damage through a RAGE-dependent mechanism, suggesting that AGEs may promote the generation of an oxidative stress vicious cycle, which can explain the severe progression of patients with both pathologies.
Valente
Tony
T
Department of Biochemistry and Molecular Biology, School of Medicine, Neuroscience Institute, Autonomous University of Barcelona, Bellaterra-08193, Barcelona, Spain. tonyvalente@gmail.com
Gella
Alejandro
A
Fernàndez-Busquets
Xavier
X
Unzeta
Mercedes
M
Durany
Nuria
N
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D052160:Benzothiazoles; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002452:Cell Count; D003920:Diabetes Mellitus / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005455:Fluorescent Antibody Technique; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D010446:Peptide Fragments / Q000378:metabolism*; D037121:Plant Lectins; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D013844:Thiazoles; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D017127:Glycation End Products, Advanced; C054369:MAPT protein, human; D010446:Peptide Fragments; D037121:Plant Lectins; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D013844:Thiazoles; C078592:amyloid beta-protein (1-40); D016875:tau Proteins; C034981:tomato lectin; C009462:thioflavin T