Dityrosine cross-linking and its potential roles in Alzheimer's disease

Abstract

Oxidative stress is a significant source of damage that accumulates during aging and contributes to Alzheimer's disease (AD) pathogenesis. Oxidation of proteins can give rise to covalent links between adjacent tyrosines known as dityrosine (DiY) cross-linking, amongst other modifications, and this observation suggests that DiY could serve as a biomarker of accumulated oxidative stress over the lifespan. Many studies have focused on understanding the contribution of DiY to AD pathogenesis and have revealed that DiY crosslinks can be found in both Aβ and tau deposits - the two key proteins involved in the formation of amyloid plaques and tau tangles, respectively. However, there is no consensus yet in the field on the impact of DiY on Aβ and tau function, aggregation, and toxicity. Here we review the current understanding of the role of DiY on Aβ and tau gathered over the last 20 years since the first observation, and discuss the effect of this modification for Aβ and tau aggregation, and its potential as a biomarker for AD.

Keywords: Alzheimer’s disease; amyloid-beta; dityrosine; oxidative; tau.

FIGURE 1

Dityrosine: (A) Chemical structure and molecular formula of dityrosine produced from two tyrosine amino acids. (B) Schematic shows depiction of crosslinking of two β-sheet rich protein molecules.

FIGURE 2

Aβ1–42 generation from amyloid precursor protein (APP). β-secretase cleavage beside aspartic acid and cleavage by γ-secretase can generate Aβ1–42 as well as other alternative length Aβ peptides. Amino acids are depicted as circles. Tyrosine (Y10) is able to form dityrosine cross-links and is highlighted in pink.

FIGURE 3

The tau gene has 16 exons; exon 1, 4, 5, 7, 9, 11, 12, and 13 (light blue) are constitutively transcribed in the CNS (Martin et al., 2011). Exon 4A, 6, and 8 (orange) are rarely expressed in the brain but included in mRNA of most peripheral tissues, while exon 14 forms part of the 3′ untranslated region of the tau mRNA (Andreadis, 2005; Connell et al., 2005). Alternate splicing of exon 2 (blue), 3 (Green), and 10 (Yellow) in the CNS generates the widely known six isoforms of tau; 352–441 amino acids in length and 48–67 kDa on SDS-PAGE (Martin et al., 2011). Depending on the inclusion and/or exclusion of exon 2, 3, and 10, tau has zero, one or two (0/1/2) N-terminal inserts and three or four (3R/4R) microtubule binding repeats, leading to the six isoforms of tau in the CNS. Structurally, tau is subdivided into an N-terminal acidic region; proline-rich region/domain (PRD), repeat domain region, and a C-terminal region.

FIGURE 4

Cryo-electron microscopy structure of paired helical filaments (Fitzpatrick et al., 2017) 5O3L.ENT showing position of tyrosine10 in magenta. Left side view, right panel top view.