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[200117 Àú³Î¹ßÇ¥] Amyloid Beta and Tau Cooperate to Cause Reversible Behavioral and Transcriptional Deficits in a Model of Alzheimer¡¯s Disease

ÇÑÁöÈñ ¦¢ 2020-01-15

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Cell Reports
Volume 29, Issue 11, 10 December 2019, Pages 3592-3604.e5
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Article
Amyloid Beta and Tau Cooperate to Cause Reversible Behavioral and Transcriptional Deficits in a Model of Alzheimer¡¯s Disease

Under a Creative Commons license
open access

Highlights

A¥â and tau work together to cause behavioral and transcriptional deficits in mice

In mice with A¥â and tau, glial gene expression increases and synaptic genes decrease

Tau is present in synaptic terminals in APP/PS1+Tau mice and human Alzheimer brain

In mice, lowering tau levels improves cognition and restores gene expression

Summary

A key knowledge gap blocking development of effective therapeutics for Alzheimer¡¯s disease (AD) is the lack of understanding of how amyloid beta (A¥â) peptide and pathological forms of the tau protein cooperate in causing disease phenotypes. Within a mouse tau-deficient background, we probed the molecular, cellular, and behavioral disruption triggered by the influence of wild-type human tau on human A¥â-induced pathology. We find that A¥â and tau work cooperatively to cause a hyperactivity behavioral phenotype and to cause downregulation of transcription of genes involved in synaptic function. In both our mouse model and human postmortem tissue, we observe accumulation of pathological tau in synapses, supporting the potential importance of synaptic tau. Importantly, tau reduction in the mice initiated after behavioral deficits emerge corrects behavioral deficits, reduces synaptic tau levels, and substantially reverses transcriptional perturbations, suggesting that lowering synaptic tau levels may be beneficial in AD.





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