Revisiting the intersection of amyloid, pathologically modified tau and iron in Alzheimer's disease from a ferroptosis perspective

Abstract

The complexity of Alzheimer's disease (AD) complicates the search for effective treatments. While the key roles of pathologically modified proteins has occupied a central role in hypotheses of the pathophysiology, less attention has been paid to the potential role for transition metals overload, subsequent oxidative stress, and tissue injury. The association of transition metals, the major focus heretofore iron and amyloid, the same can now be said for the likely pathogenic microtubular associated tau (MAPT). This review discusses the interplay between iron, pathologically modified tau and oxidative stress, and connects many related discoveries. Basic principles of the transition to pathological MAPT are discussed. Iron, its homeostatic mechanisms, the recently described phenomenon of ferroptosis and purported, although still controversial roles in AD are reviewed as well as considerations to overcome existing hurdles of iron-targeted therapeutic avenues that have been attempted in AD. We summarize the involvement of multiple pathological pathways at different disease stages of disease progression that supports the potential for a combinatorial treatment strategy targeting multiple factors.

Keywords: Alzheimer’s disease; Ferroptosis; Iron; Reactive oxygen species; Senescence; Tau.

Figure 1.

Schematic structure of human tau (htau40).

Figure 2.

Possible pathways for generating NFTs from Oligomeric Tau.

Figure 3.

SOD Cycle and ROS-generating cycles of Fe(II)/Fe(III)

Figure 4.

Quenching of ROS by Glutathione.

Figure 5.

Schematic of import, storage and export pathways in iron metabolism.

Figure 6.

Pathways of Ferroptosis involving iron and the mitigation and fate of lipid peroxides. Adapted from Derry and Kent, 2017 and Doll and Conrad, 2017.

Figure 7.

Structures of Iron Chelators Tested in AD models.