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Cell Rep. 2019 Dec 10;29(11):3592-3604.e5. doi: 10.1016/j.celrep.2019.11.044.

Amyloid Beta and Tau Cooperate to Cause Reversible Behavioral and Transcriptional Deficits in a Model of Alzheimer's Disease.

Author information

1
The University of Edinburgh Centre for Discovery Brain Sciences, 1 George Square, Edinburgh EH8 9JZ, UK.
2
The University of Edinburgh Centre for Discovery Brain Sciences, 1 George Square, Edinburgh EH8 9JZ, UK; UK Dementia Research Institute at Edinburgh, George Square, Edinburgh EH8 9JZ, UK.
3
The University of Edinburgh Centre for Discovery Brain Sciences, 1 George Square, Edinburgh EH8 9JZ, UK; MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
4
Centre for Clinical Brain Sciences and Sudden Death Brain Bank, University of Edinburgh, Edinburgh EH16 4SB, UK.
5
McGill University Department of Psychology, Montreal QC H3A 1B1, Canada; The University of Edinburgh Simons Initiative for the Developing Brain, George Square, Edinburgh EH8 9JZ, UK.
6
The University of Edinburgh Centre for Discovery Brain Sciences, 1 George Square, Edinburgh EH8 9JZ, UK; UK Dementia Research Institute at Edinburgh, George Square, Edinburgh EH8 9JZ, UK. Electronic address: tara.spires-jones@ed.ac.uk.

Abstract

A key knowledge gap blocking development of effective therapeutics for Alzheimer's disease (AD) is the lack of understanding of how amyloid beta (Aβ) 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 Aβ-induced pathology. We find that Aβ 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.

KEYWORDS:

Alzheimer; amyloid beta; array tomography; microglia; synapse; tau

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