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      Pathological Tau Promotes Neuronal Damage by Impairing Ribosomal Function and Decreasing Protein Synthesis.

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          Abstract

          One of the most common symptoms of Alzheimer's disease (AD) and related tauopathies is memory loss. The exact mechanisms leading to memory loss in tauopathies are not yet known; however, decreased translation due to ribosomal dysfunction has been implicated as a part of this process. Here we use a proteomics approach that incorporates subcellular fractionation and coimmunoprecipitation of tau from human AD and non-demented control brains to identify novel interactions between tau and the endoplasmic reticulum (ER). We show that ribosomes associate more closely with tau in AD than with tau in control brains, and that this abnormal association leads to a decrease in RNA translation. The aberrant tau-ribosome association also impaired synthesis of the synaptic protein PSD-95, suggesting that this phenomenon contributes to synaptic dysfunction. These findings provide novel information about tau-protein interactions in human brains, and they describe, for the first time, a dysfunctional consequence of tau-ribosome associations that directly alters protein synthesis. Significance statement: Despite the identification of abnormal tau-ribosomal interactions in tauopathies >25 years ago, the consequences of this association remained elusive until now. Here, we show that pathological tau associates closely with ribosomes in AD brains, and that this interaction impairs protein synthesis. The overall result is a stark reduction of nascent proteins, including those that participate in synaptic plasticity, which is crucial for learning and memory. These data mechanistically link a common pathologic sign, such as the appearance of pathological tau inside brain cells, with cognitive impairments evident in virtually all tauopathies.

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          Author and article information

          Journal
          J. Neurosci.
          The Journal of neuroscience : the official journal of the Society for Neuroscience
          1529-2401
          0270-6474
          Jan 20 2016
          : 36
          : 3
          Affiliations
          [1 ] Sanders Brown Center on Aging.
          [2 ] Departments of Molecular and Cellular Biochemistry, and.
          [3 ] Pharmacology, Boston University School of Medicine, Boston, Massachusetts 02118, and.
          [4 ] Sanders Brown Center on Aging, Departments of Molecular and Cellular Biochemistry, and.
          [5 ] Sanders Brown Center on Aging, Department of Physiology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536-0230 joe.abisambra@uky.edu.
          Article
          36/3/1001
          10.1523/JNEUROSCI.3029-15.2016
          4719006
          26791227
          9c476732-424b-485f-96f0-d3587b981ec0
          Copyright © 2016 the authors 0270-6474/16/361001-07$15.00/0.
          History

          Alzheimer,RNA,ribosome,tau,tauopathies,translation
          Alzheimer, RNA, ribosome, tau, tauopathies, translation

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