TY - JOUR
T1 - Nonphosphorylated tau slows down Aβ1-42 aggregation, binds to Aβ1-42 oligomers, and reduces Aβ1-42 toxicity
AU - Beeg, Marten
AU - Battocchio, Elisabetta
AU - De Luigi, Ada
AU - Colombo, Laura
AU - Natale, Carmina
AU - Cagnotto, Alfredo
AU - Corbelli, Alessandro
AU - Fiordaliso, Fabio
AU - Diomede, Luisa
AU - Salmona, Mario
AU - Gobbi, Marco
N1 - Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
PY - 2021/4/19
Y1 - 2021/4/19
N2 - The formation of neurofibrillary tangles and amyloid plaques accompanies the progression of Alzheimer's disease. Tangles are made of fibrillar aggregates formed by the microtubule-associated protein tau, whereas plaques comprise fibrillar forms of amyloid-beta (Aβ). Both form toxic oligomers during aggregation and are thought to interact synergistically to each promote the accumulation of the other. Recent in vitro studies have suggested that the monomeric nonphosphorylated full-length tau protein hinders the aggregation of Aβ1-40 peptide, but whether the same is true for the more aggregation-prone Aβ1-42 was not determined. We used in vitro and in vivo techniques to explore this question. We have monitored the aggregation kinetics of Aβ1-42 by thioflavine T fluorescence in the presence or the absence of different concentrations of nonphosphorylated tau. We observed that elongation of Aβ1-42 fibrils was inhibited by tau in a dose-dependent manner. Interestingly, the fibrils were structurally different in the presence of tau but did not incorporate tau. Surface plasmon resonance indicated that tau monomers bound to Aβ1-42 oligomers (but not monomers) and hindered their interaction with the anti-Aβ antibody 4G8, suggesting that tau binds to the hydrophobic central core of Aβ recognized by 4G8. Tau monomers also antagonized the toxic effects of Aβ oligomers in Caenorhabditis elegans. This suggests that nonphosphorylated tau might have a neuroprotective effect by binding Aβ1-42 oligomers formed during the aggregation and shielding their hydrophobic patches.
AB - The formation of neurofibrillary tangles and amyloid plaques accompanies the progression of Alzheimer's disease. Tangles are made of fibrillar aggregates formed by the microtubule-associated protein tau, whereas plaques comprise fibrillar forms of amyloid-beta (Aβ). Both form toxic oligomers during aggregation and are thought to interact synergistically to each promote the accumulation of the other. Recent in vitro studies have suggested that the monomeric nonphosphorylated full-length tau protein hinders the aggregation of Aβ1-40 peptide, but whether the same is true for the more aggregation-prone Aβ1-42 was not determined. We used in vitro and in vivo techniques to explore this question. We have monitored the aggregation kinetics of Aβ1-42 by thioflavine T fluorescence in the presence or the absence of different concentrations of nonphosphorylated tau. We observed that elongation of Aβ1-42 fibrils was inhibited by tau in a dose-dependent manner. Interestingly, the fibrils were structurally different in the presence of tau but did not incorporate tau. Surface plasmon resonance indicated that tau monomers bound to Aβ1-42 oligomers (but not monomers) and hindered their interaction with the anti-Aβ antibody 4G8, suggesting that tau binds to the hydrophobic central core of Aβ recognized by 4G8. Tau monomers also antagonized the toxic effects of Aβ oligomers in Caenorhabditis elegans. This suggests that nonphosphorylated tau might have a neuroprotective effect by binding Aβ1-42 oligomers formed during the aggregation and shielding their hydrophobic patches.
KW - Amyloid/antagonists & inhibitors
KW - Amyloid beta-Peptides/antagonists & inhibitors
KW - Animals
KW - Caenorhabditis elegans/drug effects
KW - Humans
KW - Kinetics
KW - Larva/drug effects
KW - Neuroprotective Agents/pharmacology
KW - Peptide Fragments/antagonists & inhibitors
KW - tau Proteins/pharmacology
U2 - 10.1016/j.jbc.2021.100664
DO - 10.1016/j.jbc.2021.100664
M3 - Article
C2 - 33865852
VL - 296
SP - 100664
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
ER -