These authors contributed to this work equally.
Autoreactive-Aβ antibodies promote APP β-secretase processing
Article first published online: 23 JAN 2012
© 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry
Journal of Neurochemistry
Volume 120, Issue 5, pages 732–740, March 2012
How to Cite
Deng, J., Hou, H., Giunta, B., Mori, T., Wang, Y.-J., Fernandez, F., Weggen, S., Araki, W., Obregon, D. and Tan, J. (2012), Autoreactive-Aβ antibodies promote APP β-secretase processing. Journal of Neurochemistry, 120: 732–740. doi: 10.1111/j.1471-4159.2011.07629.x
- Issue published online: 10 FEB 2012
- Article first published online: 23 JAN 2012
- Accepted manuscript online: 21 DEC 2011 07:55AM EST
- Received October 4, 2011; revised manuscript received December 2, 2011; accepted December 5, 2011.
- Aβ40,42 peptides;
- Alzheimer’s disease;
- anti-N-terminal Aβ antibodies;
- APP amyloidogenic processing;
- auto-Aβ antibodies
J. Neurochem. (2012) 120, 732–740.
Several prior investigations of Alzheimer’s disease (AD) patients have indicated naturally occurring autoantibodies against amyloid-β (Aβ) species are produced. Although many studies have focused on the relative concentrations or binding affinities of autoantibodies against Aβ-related proteins in AD and aging, data regarding their functional properties are limited. It is generally believed that these antibodies act to aid in clearance of Aβ. However, as antibodies which bind to Aβ also typically bind to the parent amyloid precursor protein (APP), we reasoned that certain Aβ-targeting autoantibodies may bind to APP thereby altering its conformation and processing. Here we show for the first time, that naturally occurring Aβ-reactive autoantibodies isolated from AD patients, but not from healthy controls, promote β-secretase activity in cultured cells. Furthermore, using monoclonal antibodies to various regions of Aβ, we found that antibodies generated against the N-terminal region, especially Aβ1-17, dose dependently promoted amyloidogenic processing of APP viaβ-secretase activation. Thus, this property of certain autoantibodies in driving Aβ generation could be of etiological importance in the development of sporadic forms of AD. Furthermore, future passive or active anti-Aβ immunotherapies must consider potential off-target effects resulting from antibodies targeting the N-terminus of Aβ, as co-binding to the corresponding region of APP may actually enhance Aβ generation.