Binding of Metal-Ion-Induced Tau Oligomers to Lipid Surfaces Is Enhanced by GSK-3β-Mediated Phosphorylation

Abstract

While 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.

Role of the Lipid Membrane and Membrane Proteins in Tau Pathology

“…In mouse neuronal N2a cells expressing human 0N4R tau isoform, phosphorylated oligomeric tau is predominantly localized in the PM (Merezhko et al, 2018) and secreted across the PM through a vesicle-free pathway (Katsinelos et al, 2018). Moreover, tau phosphorylation by GSK3β does not affect 1N4R tau monomer-membrane binding but enhances tau oligomer-membrane binding in small unilamellar lipid vesicles which consist of 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) or di-palmitoylphosphatidylcholine (DPPC) (Nuebling et al, 2020).…”

Revisiting the grammar of Tau aggregation and pathology formation: how new insights from brain pathology are shaping how we study and target Tauopathies

“…On the other hand, oligomeric Tau phosphorylated by GSK3b in vitro had a higher affinity for di-palmitoylphosphatidylcholine (DPPC) or 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) unilamellar vesicles, whereas phosphorylation of monomeric 4R1N did not affect its lipid-binding affinity. 460 During apoptotic cell death phosphorylated aggregated Tau was enriched in the plasma membrane-containing PC12 cell line extracts. 461 Tau phosphorylation by Fyn kinase resulted in its recruitment and enrichment at the membrane in neuronal cells, 462 and oligomeric phosphorylated Tau was enriched at plasma membrane of human 4R0N-overexpressing murine neuronal N2a cell line.…”

Iron and Targeted Iron Therapy in Alzheimer’s Disease

“…Ahmadi et al found, through electrochemical studies, that Fe 2+ showed a more significant effect in inducing tau aggregation than Fe 3+ , and that Fe 2+ also mediates tau interactions [94]. Fe 3+ can induce the pathological enhancement of hyperphosphorylated tau oligomer function, allowing phosphorylated tau to bind to membrane lipids at nanomolar protein concentrations, exacerbating disease progression [95]. Thus, the presence of iron may have a greater impact on tau pathology than previously thought.…”