Abstract
One of the key knowledge gaps in the field of Alzheimer's disease research is the lack of understanding of how amyloid beta and tau cooperate to cause neurodegeneration. We recently generated a mouse model (APP/PS1+Tau) that develops amyloid plaque pathology and expresses human tau in the absence of endogenous murine tau. These mice exhibit an age-related behavioural hyperactivity phenotype and transcriptional deficits which are ameliorated by tau transgene suppression. We hypothesized that these mice would also display memory and hippocampal synaptic plasticity deficits as has been reported for many plaque bearing mouse models which express endogenous mouse tau. We observed that our APP/PS1+Tau model does not exhibit novel object memory or robust long-term potentiation deficits with age, whereas the parent APP/PS1 line with mouse tau did develop the expected deficits. These data are important as they highlight potential functional differences between mouse and human tau and the need to use multiple models to fully understand Alzheimer's disease pathogenesis and develop effective therapeutic strategies.
Highlights
Alzheimer’s disease (AD) is neuropathologically defined by brain atrophy and the accumulation of amyloid plaques and neurofibrillary tangles
To test the hypothesis that memory was impaired in amyloid precursor protein (APP)/presenilin 1 (PS1)+the presence of a single outlier (Tau) mice, novel object recognition memory was assessed in mice between 9 and 10.5 months of age, a time point when we previously observed a hyperactivity behavioural phenotype alongside transcriptional dysregulation ( Pickett et al, 2019)
Our previous work in the APP/PS1+Tau mouse line and human postmortem tissue indicate that both A and tau accumulate in synapses, where it may contribute to synaptic dysfunction and downstream cognitive decline (Jackson et al, 2016, 2019; Zhou et al, 2017; McInnes et al, 2018; Hesse et al, 2019; Pickett et al, 2019)
Summary
Alzheimer’s disease (AD) is neuropathologically defined by brain atrophy and the accumulation of amyloid plaques and neurofibrillary tangles. Amyloid pathology develops very early in the disease process, and rare disease-causing mutations all act through impacting amyloid beta (A ) accumulation; tau accumulation in neurofibrillary tangles is more closely associated with neurodegeneration and dementia symptoms. These data led to the theory that A initiates the disease process causing downstream changes in tau that lead to neurodegeneration (Hardy & Higgins, 1992). Several more studies suggest that lowering endogenous mouse tau levels protects against other synaptic phenotypes in mice with plaques (Ittner et al, 2010; Vossel et al, 2010; Roberson et al, 2011; DeVos et al, 2018). Recent data indicate that the interplay between A and tau is more complex than a linear cascade and likely involves glia and neuron-glia interactions (Henstridge et al, 2019)
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