Reducing tau ameliorates behavioural and transcriptional deficits in a novel model of Alzheimer’s disease

Abstract

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 CC-BY 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint .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.

Alzheimer’s disease as a synaptopathy: Evidence for dysfunction of synapses during disease progression

“…There is limited work looking at synaptic function in animal and cellular models with dual amyloid and tau pathology. In APP/PS1 mice crossed with Tau knock-out (KO) mice or Tg21221 mice which express human tau only, there was observed downregulation of synaptic genes for pathways such as for LTP, long-term depression (LTD), and glutamate receptor signaling, seen in the combined model compared to the respective controls (Pickett et al, 2019). One study examined intracellular Ca 2+ transients in a crossed model between the APP/PS1 mouse model of amyloidopathy and the rTg4510 mouse model of tauopathy and observed reduced neuronal activity, compared to the individual amyloid and tau mouse models which showed hyperexcitability and neuronal silencing, respectively (Busche et al, 2019).…”

Bringing synapses into focus: Recent advances in synaptic imaging and mass-spectrometry for studying synaptopathy

“…This allows the analysis of multiple proteins within individual synapses and has been validated for up to six stripping rounds, allowing for the identification of 18 different synaptic markers (Kleinfeld et al, 2011). Array tomography has now been widely used as a high-resolution imaging technique to study synapses in several contexts such as Alzheimer's disease (Koffie et al, 2012(Koffie et al, , 2009Tai et al, 2012;Spires-Jones and Hyman, 2014;Hesse et al, 2019;Pickett et al, 2019Pickett et al, , 2016Querol-Vilaseca et al, 2019;Rupawala et al, 2022), dementia with Lewy bodies (Colom-Cadena et al, 2017Rupawala et al, 2022) and ALS (Henstridge et al, 2018). Collectively, these studies (and others) have highlighted changes in synaptic density, molecular composition, and the aggregation of disease-associated proteins in the synapse.…”