Reducing tau ameliorates behavioural and transcriptional deficits in a novel model of Alzheimer's disease
Eleanor K Pickett,
Abigail G Herrmann,
Owen R Dando,
Christopher M Henstridge,
Posted 16 Aug 2018
bioRxiv DOI: 10.1101/393405
Posted 16 Aug 2018
One of the key knowledge gaps blocking development of effective therapeutics for Alzheimer's disease (AD) is the lack of understanding of how amyloid beta (Aβ) and tau cooperate in causing disease phenotypes. Within a mouse tau deficient background, we probed the molecular, cellular and behavioural disruption triggered by wild-type human tau's influence on human Aβ-induced pathology. We find that Aβ and tau work cooperatively to cause a hyperactivity phenotype and to cause downregulation of gene transcription including many involved in synaptic function. In both our mouse model and in human post-mortem tissue, we observe accumulation of pathological tau in synapses, supporting the potential importance of synaptic tau. Importantly, tau depletion in the mice, initiated after behavioural deficits emerge, was found to correct behavioural deficits, reduce synaptic tau levels, and substantially reverse transcriptional perturbations, suggesting that lowering tau levels, particularly at the synapse, may be beneficial in AD.
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