title: Pathological Tau Promotes Neuronal Damage by Impairing Ribosomal Function and Decreasing Protein Synthesis.
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.
authors.affiliation: Sanders Brown Center on Aging.
authors.forename: Shelby
authors.initials: S
authors.lastname: Meier
authors.affiliation: Sanders Brown Center on Aging.
authors.forename: Michelle
authors.initials: M
authors.lastname: Bell
authors.affiliation: Sanders Brown Center on Aging.
authors.forename: Danielle N
authors.initials: DN
authors.lastname: Lyons
authors.affiliation: Sanders Brown Center on Aging.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rodriguez-Rivera
authors.affiliation: Sanders Brown Center on Aging.
authors.forename: Alexandria
authors.initials: A
authors.lastname: Ingram
authors.affiliation: Sanders Brown Center on Aging.
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Fontaine
authors.affiliation: Sanders Brown Center on Aging.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Mechas
authors.affiliation: Departments of Molecular and Cellular Biochemistry, and.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Pharmacology, Boston University School of Medicine, Boston, Massachusetts 02118, and.
authors.forename: Benjamin
authors.identifier: http://orcid.org/0000-0003-2068-1475
authors.initials: B
authors.lastname: Wolozin
authors.affiliation: Sanders Brown Center on Aging, Departments of Molecular and Cellular Biochemistry, and.
authors.forename: Harry
authors.initials: H
authors.lastname: LeVine
authors.affiliation: Departments of Molecular and Cellular Biochemistry, and.
authors.forename: Haining
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Sanders Brown Center on Aging, Department of Physiology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536-0230 joe.abisambra@uky.edu.
authors.forename: Jose F
authors.identifier: http://orcid.org/0000-0001-6341-679X
authors.initials: JF
authors.lastname: Abisambra
mesh_terms: D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008297:Male; D008861:Microsomes / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D014176:Protein Biosynthesis / Q000502:physiology*; D012270:Ribosomes / Q000502:physiology*; D024801:Tauopathies / Q000378:metabolism / Q000473:pathology; D016875:tau Proteins / Q000096:biosynthesis*
chemical_list: D016875:tau Proteins
keywords: Alzheimer; RNA; ribosome; tau; tauopathies; translation