P3‐060: Soluble Aβ promotes wild‐type tau pathology in vivo

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 on in vitro approaches 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 pathology in vivo. The 3xTg-AD model provided new insight into the in vivo mechanisms by which Aβ facilitates tau pathology, yet the relevant importance of soluble versus insoluble Aβ species in this process remains unclear. 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 in these “Arc tau” mice decreases soluble Aβ oligomers, rescues cognition, and more importantly also reduces tau accumulation and phosphorylation. These studies provide critical in vivo evidence for a strong mechanistic link between soluble oligomeric Aβ and tau pathology.