Prion-like seeding and nucleation of intracellular amyloid-β

Alzheimer's disease (AD) brain tissue can act as a seed to accelerate aggregation of amyloid-beta (A beta) into plaques in AD transgenic mice. A beta seeds have been hypothesized to accelerate plaque formation in a prion-like manner of templated seeding and intercellular propagation. However, the structure(s) and location(s) of the A beta seeds remain unknown. Moreover, in contrast to tau and alpha-synuclein, an in vitro system with prion-like AO has not been reported. Here we treat human APP expressing N2a cells with AD transgenic mouse brain extracts to induce inclusions of A beta in a subset of cells. We isolate cells with induced All inclusions and using immunocytochemistry, western blot and infrared spectroscopy show that these cells produce oligomeric A beta over multiple replicative generations. Further, we demonstrate that cell lysates of clones with induced oligomeric A beta can induce aggregation in previously untreated N2a APP cells. These data strengthen the case that A beta acts as a prion-like protein, demonstrate that A beta seeds can be intracellular oligomers and for the first time provide a cellular model of nucleated seeding of A beta.