Premium
P2‐072: SYNTHESIS AND BIOLOGICAL ACTIVITIES OF THE Aβ40 DIMER WITH TOXIC CONFORMATION
Author(s) -
Irie Kazuhiro,
Murakami Kazuma,
Suzuki Takashi,
Sato Mizuho,
Iwasaki Mami,
Kume Toshiaki
Publication year - 2014
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2014.05.746
Subject(s) - trimer , dimer , chemistry , tetramer , conformational isomerism , oligomer , covalent bond , neurotoxicity , thioflavin , stereochemistry , molecule , organic chemistry , alzheimer's disease , toxicity , medicine , disease , pathology , enzyme
brains, tau associates with ribosomes and facilitates de novo protein biosynthesis.Methods:We performed subcellular fractionation of human AD and control brains coupled with tandem mass spectrometry peptide identification. We transduced primary neurons with lentiviral particles coding for various pathological tau species to evaluate ribosome transport dynamics in microfluidic chambers; we applied a novel microscopy approach for live-cell imaging and 3D rendering. We performed cell-free assays to survey specific functions of cellular components. Finally, we used chemical manipulations to test tau-mediated alterations to the ribosome. Results:We identified that in human AD and normal brain, tau associates with ER-associated proteins, the majority of which correspond to ribosomal protein complexes. Under normal conditions, tau enhanced protein biosynthesis; conversely, pathological tau species associated more robustly with ribosomes and abrogated their efficiency. The mechanism of tau-mediated ribosomal dysfunction involved ribosomal transport and intrinsic abrogation of RNA translation. Finally, tau associated with a subset of the ribosome-binding protein complex. Conclusions: We present a novel tau function as it relates to the promotion of protein biosynthesis in the brain. In contrast, pathological tau perturbs ribosomal function by two mechanisms, and the result is impaired protein production. Since protein biosynthesis is necessary for memory formation, our work establishes a direct link between tau aberrations and memory impairment. These data support the exploration of the tau-ribosome complex for therapeutic target identification, and it opens a new window of treatment strategies for tauopathies.