Autoreactive-Aβ antibodies promote APP β-secretase processing

Several prior investigations of Alzheimers disease (AD) patients have indicated naturally occurring autoantibodies against amyloid-beta (A beta) species are produced. Although many studies have focused on the relative concentrations or binding affinities of autoantibodies against A beta-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 A beta. However, as antibodies which bind to A beta also typically bind to the parent amyloid precursor protein (APP), we reasoned that certain A beta-targeting autoantibodies may bind to APP thereby altering its conformation and processing. Here we show for the first time, that naturally occurring A beta-reactive autoantibodies isolated from AD patients, but not from healthy controls, promote beta-secretase activity in cultured cells. Furthermore, using monoclonal antibodies to various regions of A beta, we found that antibodies generated against the N-terminal region, especially A beta 1-17, dose dependently promoted amyloidogenic processing of APP via beta-secretase activation. Thus, this property of certain autoantibodies in driving A beta generation could be of etiological importance in the development of sporadic forms of AD. Furthermore, future passive or active anti-A beta immunotherapies must consider potential off-target effects resulting from antibodies targeting the N-terminus of A beta, as co-binding to the corresponding region of APP may actually enhance A beta generation.