Soluble Aβ Promotes Wild-Type Tau Pathology In Vivo

Growing evidence suggests that soluble A beta species can drive Alzheimer disease (AD) pathogenesis by inducing a cascade of events including tau hyperphosphorylation, proteasome impairment, and synaptic dysfunction. However, these studies have relied largely on in vitro approaches to examine the role of soluble A beta in AD. In particular, it remains unknown whether soluble A beta oligomers can facilitate the development of human wild-type tau pathology in vivo. To address this question, we developed a novel transgenic model that expresses low levels of APP with the Arctic familial AD mutation to enhance soluble A beta oligomer formation in conjunction with wild-type human tau. Using a genetic approach, we show that reduction of beta-site APP cleaving enzyme (BACE) in these ArcTau mice decreases soluble A beta oligomers, rescues cognition, and, more importantly, reduces tau accumulation and phosphorylation. Notably, BACE reduction decreases the postsynaptic mislocalization of tau in ArcTau mice and reduces the association between NMDA receptors and PSD-95. These studies provide critical in vivo evidence for a strong mechanistic link between soluble A beta, wild-type tau, and synaptic pathology.