Soluble Aβ Promotes Wild-Type Tau PathologyIn Vivo

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Abstract
Growing evidence suggests that soluble Aβ 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 onin vitroapproaches to examine the role of soluble Aβ in AD. In particular, it remains unknown whether soluble Aβ oligomers can facilitate the development of human wild-type tau pathologyin 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 Aβ oligomer formation in conjunction with wild-type human tau. Using a genetic approach, we show that reduction of β-site APP cleaving enzyme (BACE) in these ArcTau mice decreases soluble Aβ 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 criticalin vivoevidence for a strong mechanistic link between soluble Aβ, wild-type tau, and synaptic pathology.

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