TY - JOUR
T1 - Autoantibodies to amyloid β-peptide (Aβ) are increased in Alzheimer's disease patients and Aβ antibodies can enhance Aβ neurotoxicity
T2 - Implications for disease pathogenesis and vaccine development
AU - Nath, Avindra
AU - Hall, Elizabeth
AU - Tuzova, Marnia
AU - Dobbs, Michael
AU - Jones, Melina
AU - Anderson, Caroline
AU - Woodward, Jerold
AU - Guo, Zhihong
AU - Fu, Weiming
AU - Kryscio, Richard
AU - Wekstein, David
AU - Smith, Charles
AU - Markesbery, William R.
AU - Mattson, Mark P.
PY - 2003
Y1 - 2003
N2 - Studies of amyloid precursor protein transgenic mice suggest that immune responses to amyloid β peptide (Aβ) may be instrumental in the removal of plaques from the brain, but the initial clinical trial of an Aβ 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 Aβ and that, contrary to expectations, Aβ antibodies enhance the neurotoxic activity of the peptide. Serum titers to Aβ were significantly elevated in AD patients and Aβ antibodies were found in association with amyloid plaques in their brains, but there was no evidence of cell-mediated immune responses to Aβ in the patients. Aβ antibodies were detected in the serum of old APP mutant transgenic mice with plaque-like Aβ deposits, but not in the serum of younger transgenic or nontransgenic mice. Serum from APP mutant mice potentiated the neurotoxicity of Aβ. Our data suggest that a humoral immune response to Aβ in AD patients may promote neuronal degeneration, a process with important implications for the future of vaccine-based therapies for AD.
AB - Studies of amyloid precursor protein transgenic mice suggest that immune responses to amyloid β peptide (Aβ) may be instrumental in the removal of plaques from the brain, but the initial clinical trial of an Aβ 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 Aβ and that, contrary to expectations, Aβ antibodies enhance the neurotoxic activity of the peptide. Serum titers to Aβ were significantly elevated in AD patients and Aβ antibodies were found in association with amyloid plaques in their brains, but there was no evidence of cell-mediated immune responses to Aβ in the patients. Aβ antibodies were detected in the serum of old APP mutant transgenic mice with plaque-like Aβ deposits, but not in the serum of younger transgenic or nontransgenic mice. Serum from APP mutant mice potentiated the neurotoxicity of Aβ. Our data suggest that a humoral immune response to Aβ in AD patients may promote neuronal degeneration, a process with important implications for the future of vaccine-based therapies for AD.
KW - Apoptosis
KW - Hippocampal
KW - Immune
KW - Secretase
KW - Transgenic
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UR - http://www.scopus.com/inward/citedby.url?scp=0037610172&partnerID=8YFLogxK
U2 - 10.1385/NMM:3:1:29
DO - 10.1385/NMM:3:1:29
M3 - Article
C2 - 12665674
AN - SCOPUS:0037610172
SN - 1535-1084
VL - 3
SP - 29
EP - 39
JO - NeuroMolecular Medicine
JF - NeuroMolecular Medicine
IS - 1
ER -