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Binding of Metal-Ion-Induced Tau Oligomers to Lipid Surfaces Is Enhanced by GSK-3β-Mediated Phosphorylation
journal contribution
posted on 2020-02-28, 16:43 authored by Georg
S. Nuebling, Eva Plesch, Viktoria C. Ruf, Tobias Högen, Stefan Lorenzl, Frits Kamp, Armin Giese, Johannes LevinWhile
fibrillar deposits of hyperphosphorylated protein tau are
a key hallmark of several neurodegenerative diseases such as Alzheimer’s
disease, small oligomers have been speculated to be the key toxic
aggregate species. Trivalent metal ions were shown to promote tau
oligomer formation in vitro. However, little is known
about potential intercellular spreading mechanisms or toxic modes
of action of such oligomers. We investigated interactions of tau monomers
and Fe3+/Al3+-induced oligomers with small unilamellar
vesicles derived from 1-palmitoyl-2-oleoyl-phosphatidylcholine (neutral,
liquid-crystalline phase) and dipalmitoyl-phosphatidylcholine (neutral,
gel-phase). We further evaluated the influence of glycogen synthase
kinase 3β (GSK-3β)-mediated tau phosphorylation applying
the single-particle fluorescence spectroscopy techniques fluorescence
correlation spectroscopy, fluorescence intensity distribution analysis,
and scanning for intensely fluorescent targets. In these experiments,
no binding to neutral lipid surfaces was observed for tau monomers.
In contrast, metal-ion-induced tau oligomers showed a gain of function
in binding to neutral lipid surfaces. Of note, tau phosphorylation
by GSK-3β increased both oligomer formation and membrane affinity
of the resulting oligomers. In conclusion, our data imply a pathological
gain of function of metal-ion-induced oligomers of hyperphosphorylated
tau, enabling membrane binding irrespective of surface charge even
at nanomolar protein concentrations.
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Keywords
glycogen synthase kinase 3βGSK -3β-Mediated PhosphorylationTrivalent metal ionsMetal-Ion-Induced Tau Oligomerslipid surfacesnanomolar protein concentrationsmetal-ion-induced tau oligomerstau monomerstau oligomer formationbindingfluorescence intensity distribution analysis1- palmitoyl -2-oleoylsingle-particle fluorescence spectroscopy techniques fluorescence correlation spectroscopyhyperphosphorylated protein tau
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