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Updated: May 16, 2026
Cell-based Assay to Study Antibody-mediated Tau Clearance by Microglia
Published on: November 9, 2018
Soluble aβ promotes wild-type tau pathology in vivo
Meredith A Chabrier1, Mathew Blurton-Jones, Andranik A Agazaryan
1Department of Neurobiology and Behavior, Institute for Memory Impairment and Neurological Disorders, and Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, California 92697, USA.
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. 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 critical in vivo evidence for a strong mechanistic link between soluble Aβ, wild-type tau, and synaptic pathology.
Insights
Soluble amyloid-beta (Aβ) oligomers drive Alzheimer disease (AD) tau pathology and synaptic dysfunction in vivo. Reducing BACE enzyme activity in a novel mouse model ameliorates these AD-like changes.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Soluble amyloid-beta (Aβ) species are implicated in Alzheimer disease (AD) pathogenesis, including tau hyperphosphorylation and synaptic dysfunction.
- Previous studies primarily used in vitro methods, leaving the in vivo role of soluble Aβ oligomers in human wild-type tau pathology unclear.
Purpose of the Study:
- To investigate whether soluble Aβ oligomers can induce human wild-type tau pathology in vivo.
- To establish a novel transgenic mouse model for studying the interplay between Aβ and tau.
Main Methods:
- Developed a transgenic ArcTau mouse model expressing Arctic familial AD mutation APP with wild-type human tau.
- Utilized a genetic approach to reduce β-site APP cleaving enzyme (BACE) activity in ArcTau mice.
- Assessed cognitive function, Aβ oligomer levels, tau phosphorylation, and synaptic protein associations.
Main Results:
- Reduction of BACE activity decreased soluble Aβ oligomers and rescued cognitive deficits in ArcTau mice.
- BACE reduction significantly lowered tau accumulation and hyperphosphorylation.
- Importantly, BACE inhibition prevented postsynaptic mislocalization of tau and reduced NMDA receptor-PSD-95 association.
Conclusions:
- Provides critical in vivo evidence linking soluble Aβ oligomers to wild-type tau pathology and synaptic dysfunction.
- Demonstrates that targeting BACE can ameliorate Aβ-induced tauopathy and synaptic deficits in a relevant AD model.
- Highlights a mechanistic connection between soluble Aβ, tau, and synaptic pathology in Alzheimer disease pathogenesis.
