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.
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The University of Kentucky Alzheimer's Disease Center (UK-ADC) and its Neuropathology Core is supported by NIH/NIA P30 AG028383; the University of Kentucky Proteomics Core is partially supported by grants from the NIH/NIGMS (P20GM103486) and the NIH/NCI (P30CA177558); this work was also supported in part by NIH R01NS077284 (H.Z.); the LC-MS/MS instrument was acquired with a High-End Instrumentation Grant S10RR029127 (H.Z.) from the National Institutes of Health; NIH/NINDS P30NS051220 supported the maintenance of the microscopy core used for imaging; J.F.A., D.L., and S.M. were supported by NIH/NINDS 1R01 NS091329-01, Alzheimer's Association NIRG-14-322441, NIH/NCATS 5UL1TR000117-04, NIH/NIGMS 5P30GM110787, GlaxoSmithKline, Department of Defense AZ140097, UK-ADC Pilot Award 8.1 supported by NIH/NIA P30 AG028383, the University of Kentucky Epilepsy Center and NIH/NIMHD L32 MD009205-01.
Meier, Shelby; Bell, Michelle; Lyons, Danielle N.; Rodriguez-Rivera, Jennifer; Ingram, Alexandria; Fontaine, Sarah N.; Mechas, Elizabeth; Chen, Jing; Wolozin, Benjamin; LeVine, Harry III; Zhu, Haining; and Abisambra, Jose F., "Pathological Tau Promotes Neuronal Damage by Impairing Ribosomal Function and Decreasing Protein Synthesis" (2016). Sanders-Brown Center on Aging Faculty Publications. 76.