Autoimmunity in Alzheimer's disease as evidenced by plasma immunoreactivity against RAGE and Abeta42: complication of diabetes.
Features of autoimmunity have been associated with both Alzheimer's disease (AD) and with diabetes. In both diseases high levels of advanced glycation end products (AGEs) and their receptor (RAGE) have been detected in tissues and in the circulation. In addition high titers of antibodies directed against a RAGE-like peptide occur in the circulation. In this study we report the presence of auto-antibodies directed against RAGE and the cytotoxic amyloid peptide Abeta42 in plasma samples derived from four study groups. Anti-RAGE IgG titers were greatest in the AD-diabetic cohort. They were followed in decreasing order by the AD-non-diabetic cohort, the elderly diabetic cohort, and lastly by the control non-diabetic elderly cohort. The same profile of IgG differences was evident for the anti-Abeta42 titers. When all of the data were combined, there was a strong linear correlation between the RAGE and Abeta42 titers suggesting that the two peptides exist as a tight complex in plasma. Plasma IgG titers were not correlated with cognitive status except that AD and AD-diabetic participants were significantly cognitively impaired relative to the two non-AD groups. There also was no significant correlation between IgG titers and subject age, except that there was a trend for a negative slope for the AD participants and a positive slope for the control participants. In keeping with the human data, we also report that chemically-induced diabetes in rats was associated with high levels of AGEs, anti-RAGE-like IgGs, and anti-Abeta42-like IgGs. For non-diabetic rats, there was a clear age-dependency regarding the magnitude of the IgG levels. These data support the concept of an interrelationship between diabetes and AD. For both diseases one underlying contributing factor to cytotoxicity could be the development of an autoimmune response triggered by the presence of AGEs and amyloid peptides.
Mruthinti
Shyamala
S
Alzheimer's Research Center, Department of Pharmacology and Toxicology, Medical College of GA, Augusta, Georgia 30912, USA. jbuccafu@mail.mcg.edu
Schade
Rosann F
RF
Harrell
Dean U
DU
Gulati
Nidhi K
NK
Swamy-Mruthinti
S
S
Lee
Gregory P
GP
Buccafusco
Jerry J
JJ
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood / Q000150:complications / Q000276:immunology*; D016229:Amyloid beta-Peptides / Q000276:immunology*; D000818:Animals; D001323:Autoantibodies / Q000097:blood; D015551:Autoimmunity / Q000276:immunology*; D016022:Case-Control Studies; D003071:Cognition / Q000502:physiology; D048909:Diabetes Complications / Q000097:blood / Q000276:immunology; D003920:Diabetes Mellitus / Q000097:blood / Q000276:immunology*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000276:immunology; D005260:Female; D017127:Glycation End Products, Advanced / Q000097:blood / Q000276:immunology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000276:immunology*; D012016:Reference Values
D016229:Amyloid beta-Peptides; D001323:Autoantibodies; D017127:Glycation End Products, Advanced; D010446:Peptide Fragments; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic