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- W2536691301 abstract "In Alzheimer’s Disease (AD), synapse loss is the strongest pathological correlate of cognitive decline. Much work over the past 2 decades has focused on roles of amyloid beta in synapse degeneration. More recently, we and others have observed that pathological forms of tau are also synaptotoxic and can spread through synaptic circuits. In this presentation, we present new data examining the trans-synaptic spread of tau and the role of tau in synaptotoxicity. Using novel mouse models of Alzheimer’s disease and human postmortem tissue, we have examined synapses with array tomography, a high-resolution imaging technique. This method allows detection of proteins, including tau, within individual pre and postsynaptic terminals, which allows us to determine whether tau spreads from pre to postsynaptic terminals and whether it is associated with synaptotoxicity. Genetic tools such as reversibly overexpressing human tau, removal of endogenous mouse tau, and crossing these lines with amyloid models further tease out the contributions of tau to neurodegeneration and spread of disease through the brain. These studies find tau propagation from entorhinal cortex neurons to postsynapses in the middle molecular layer of the dentate gyrus before synapses or neurons are lost. Crossing tau overexpressing mice with plaque bearing animal models reveals a complex interplay between these pathological proteins with acceleration of tau propagation and exacerbation of plaque size and plaque-related neuritic changes. Conversely, lowering endogenous tau levels prevents some of the plaque-associated phenotypes. Human postmortem studies confirm the presence of tau in pre and post synaptic terminals in AD brain, and indicate that tau and amyloid beta oligomers are present in some of the same synaptic compartments. These data indicate that the characteristic spread of tau pathology through the brain in AD patients occurs via synaptic circuits early in the disease process before substantial synaptic or neuronal loss. Further, both the spread and toxicity of tau are likely linked to the accumulation of amyloid beta." @default.
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- W2536691301 date "2016-07-01" @default.
- W2536691301 modified "2023-09-27" @default.
- W2536691301 title "EC-03-03: Tau Spreading and Toxicity" @default.
- W2536691301 doi "https://doi.org/10.1016/j.jalz.2016.06.2381" @default.
- W2536691301 hasPublicationYear "2016" @default.
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