INTERACTIONS OF ABETA AND TAU IN SYNAPSE LOSS

Abstract

The collapse of neural networks important for memory and cognition, including death of neurons and degeneration of synapses, causes the debilitating dementia associated with Alzheimer's disease (AD). We have demonstrated that synaptic changes are central to the disease process. Using transgenic animal models expressing APPSwe/PS1dE9, Tg21221 wild-type human tau, and Tg4510 P301L mutant tau, and mice lacking endogenous mouse tau expression, we examined cognitive deficits and the accumulation of pathology and synapse degeneration using high-resolution imaging techniques. We further examined human postmortem brain tissue using array tomography, transmission electron microscopy, and standard stereological techniques to assess synapse degeneration. Both amyloid beta and tau proteins independently contribute to synaptic dysfunction and collapse in transgenic models of AD and frontotemporal dementia. Our recent data from a novel model of Alzheimer's disease combining APPSwe/PS1dE9 and rTg21221 expression on a mouse tau null background indicate that tau and amyloid beta are likely on the same pathway to synapse degeneration. Further, postmortem studies of human brain tissue support a role for both of these proteins in synapse collapse. Understanding mechanisms of synaptic dysfunction and loss will be critical for developing effective synapse-directed therapeutics. Acknowledgements: Funding provided by the European Research Council, Alzheimer's Research UK and the Scottish Government, Alzheimer's Society, a University of Edinburgh Wellcome Trust ISSF, NIH, and an anonymous foundation.