This paper from India, already 3 years old, is experimental but IMO could be on its way to supporting ATH434 in treating AD.

ACS Chem Neurosci

. 2021 Dec 1;12(23):4393-4405.

doi: 10.1021/acschemneuro.1c00377. Epub 2021 Nov 16.

Contrasting Effects of Ferric and Ferrous Ions on Oligomerization and Droplet Formation of Tau: Implications in Tauopathies and Neurodegeneration

Sandipan Mukherjee ¹, Dulal Panda ^{1 2}

Affiliations Expand

• PMID: 34783530

DOI: 10.1021/acschemneuro.1c00377

Abstract

The dysregulation of metal homeostasis is reported to enhance the aggregation of tau, a key neuronal microtubule-associated protein. Herein, we found that ferric (Fe³⁺) ions enhanced tau aggregation. Fe³⁺ and Al³⁺ induced tau aggregation while several trivalent metal ions such as Cr³⁺, La³⁺, and V³⁺ had no discernable effect on tau aggregation. Fe³⁺ reduced the critical concentration of tau required for the liquid-liquid phase separation (LLPS); however, Cr³⁺, La³⁺, and V³⁺ did not affect tau droplet formation. Dynamic light scattering, atomic force microscopic, and transmission electron microscopic analysis suggested that Fe³⁺ significantly increased the formation of tau oligomers and fibrils. In contrast, Fe²⁺ neither enhanced tau droplet formation nor increased the heparin-induced aggregation of tau. Using a tryptophan mutant (Y310W-tau) of tau, Fe³⁺ was found to bind to tau with four times higher affinity than Fe²⁺. Acrylamide quenching of the tryptophan fluorescence of Y310W-tau, 1-anilino-8-naphthalene sulfonate (ANS) fluorescence experiment, and far-UV circular dichroism analysis indicated that Fe³⁺ decreased the solvent exposure of the tryptophan residue, perturbed the hydrophobic surface arrangement, and disrupted the secondary structure of tau, respectively. The increase in the β-sheet content and a subsequent decrease in the disordered content of tau due to the binding of Fe³⁺ may favor tau aggregation. Fe³⁺ may enhance and stabilize the non-covalent interactions between disordered domains of tau molecules leading to tau aggregation. The data highlighted the relationship between the dysregulation of ferric ions and neurodegenerative disorders.

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