Soluble Aβ Promotes Wild-Type Tau Pathology in vivo

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...

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Bibliographic Details
Published in:Journal of Neuroscience
Main Authors: Chabrier, Meredith A., Blurton-Jones, Mathew, Agazaryan, Andranik A., Nerhus, Joy L., Martinez-Coria, Hilda, LaFerla, Frank M.
Format: Text
Language:English
Published: 2012
Subjects:
Article
Arctic
Online Access:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3586232
http://www.ncbi.nlm.nih.gov/pubmed/23197725
https://doi.org/10.1523/JNEUROSCI.0172-12.2012
Description
Summary: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. 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 also 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 Aβ, wild-type tau and synaptic pathology.

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