SummaryOne of the key knowledge gaps blocking development of effective therapeutics for Alzheimer's disease (AD) is the lack of understanding of how amyloid beta (Aß) 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 Aß-induced pathology.We find that Aß 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.. CC-BY 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/393405 doi: bioRxiv preprint first posted online Aug. 16, 2018; 2 Highlights -Expression of human familial Alzheimer's associated mutant amyloid precursor protein and presenillin 1 with wild-type human tau in the absence of endogenous tau in a novel MAPT-AD mouse model results in behavioural deficits and downregulation of genes involved in synaptic function -Tau is present in pre and postsynaptic terminals in MAPT-AD mice and human AD brain. In mice, lowering synaptic tau levels was associated with improved cognition and recovered gene expression.-These data suggest that Aß and tau act cooperatively in impairing synaptic function and that lowering tau at synapses could be a beneficial therapeutic approach in AD.