Autoantibodies to amyloid beta-peptide (Abeta) are increased in Alzheimer's disease patients and Abeta antibodies can enhance Abeta neurotoxicity: implications for disease pathogenesis and vaccine development.
Studies of amyloid precursor protein transgenic mice suggest that immune responses to amyloid beta peptide (Abeta) may be instrumental in the removal of plaques from the brain, but the initial clinical trial of an Abeta vaccine in patients with Alzheimer s disease (AD) was halted as the result of serious neurological complications in some patients. We now provide evidence that AD patients exhibit an enhanced immune response to Abeta and that, contrary to expectations, Abeta antibodies enhance the neurotoxic activity of the peptide. Serum titers to Abeta were significantly elevated in AD patients and Abeta antibodies were found in association with amyloid plaques in their brains, but there was no evidence of cell-mediated immune responses to Abeta in the patients. Abeta antibodies were detected in the serum of old APP mutant transgenic mice with plaque-like Abeta deposits, but not in the serum of younger transgenic or nontransgenic mice. Serum from APP mutant mice potentiated the neurotoxicity of Abeta. Our data suggest that a humoral immune response to Abeta in AD patients may promote neuronal degeneration, a process with important implications for the future of vaccine-based therapies for AD.
Nath
Avindra
A
Department of Neurology, University of Kentucky, Lexington, KY 40536, USA.
Hall
Elizabeth
E
Tuzova
Marnia
M
Dobbs
Michael
M
Jons
Melina
M
Anderson
Caroline
C
Woodward
Jerold
J
Guo
Zhihong
Z
Fu
Weiming
W
Kryscio
Richard
R
Wekstein
David
D
Smith
Charles
C
Markesbery
William R
WR
Mattson
Mark P
MP
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood* / Q000134:cerebrospinal fluid / Q000276:immunology*; D016229:Amyloid beta-Peptides / Q000276:immunology / Q000633:toxicity*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000276:immunology; D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000134:cerebrospinal fluid / Q000633:toxicity*; D001921:Brain / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D004347:Drug Interactions / Q000276:immunology; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000633:toxicity; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001323:Autoantibodies; D007074:Immunoglobulin G