Zinc-induced heterodimer formation between metal-binding domains of intact and naturally modified amyloid-beta species: implication to amyloid seeding in Alzheimer’s disease?

Abstract

Zinc ions and modified amyloid-beta peptides (Aβ) play a critical role in the pathological aggregation of endogenous Aβ in Alzheimer's disease (AD). Zinc-induced Aβ oligomerization is mediated by the metal-binding domain (MBD) which includes N-terminal residues 1-16 (Aβ1-16). Earlier, it has been shown that Aβ1-16 as well as some of its naturally occurring variants undergoes zinc-induced homodimerization via the interface in which zinc ion is coordinated by Glu11 and His14 of the interacting subunits. In this study using surface plasmon resonance technique, we have found that in the presence of zinc ions Aβ1-16 forms heterodimers with MBDs of two Aβ species linked to AD: Aβ containing isoAsp7 (isoAβ) and Aβ containing phosphorylated Ser8 (pS8-Aβ). The heterodimers appear to possess the same interface as the homodimers. Simulation of 200 ns molecular dynamic trajectories in two constructed models of dimers ([Aβ1-16/Zn/Aβ1-16] and [isoAβ1-16/Zn/Aβ1-16]), has shown that conformational flexibility of the N-terminal fragments of the dimer subunits is controlled by the structure of corresponding sites 6-8. The data suggest that isoAβ and pS8-Aβ can be involved in the AD pathogenesis by means of their zinc-dependent interactions with endogenous Aβ resulting in the formation of heterodimeric seeds for amyloid aggregation.

Phosphorylation of the Amyloid-Beta Peptide Inhibits Zinc-Dependent Aggregation, Prevents Na,K-ATPase Inhibition, and Reduces Cerebral Plaque Deposition

“…This may be due to the fact that pS8-Aβ 42 forms zinc-induced heterodimers with the unmodified Aβ 42 , which are not capable of further aggregation. Formation of heterodimers between the metal-binding domains of Aβ and pS8-Aβ was previously observed in vitro (Mezentsev et al, 2016). …”

“…Moreover, the zinc-driven heterodimers formed between pS8-Aβ 16 and isoD7-Aβ 16 or Aβ 16 also cannot oligomerize. We hypothesized that pS8-Aβ 42 does not aggregate in the presence of zinc ions and that pS8-Aβ 42 can prevent the aggregation of native Aβ through the formation of non-propagating heterodimers between pS8-Aβ 42 and Aβ (Mezentsev et al, 2016). By contrast, phosphorylation at Ser8 may change the interaction of Aβ with other proteins, such as Na + ,K + -ATPase.…”

Copper Toxicity Links to Pathogenesis of Alzheimer’s Disease and Therapeutics Approaches

“…Multivalent metal ions such as copper (Cu) [ 64 , 65 , 66 ], zinc (Zn) [ 67 , 68 ], and iron (Fe) [ 69 , 70 ] are reported to be at higher levels in Alzheimer’s senile plaques [ 71 , 72 ]; while the connection of these metal ions with Aβ aggregation is still not well known. Indeed, some evidence from transgenic animal studies shows that Cu accumulates in senile plaques in the brains of 5 × FAD and Tg-SwDI/NOS2−/− mice models with neurodegeneration, as compared to PSAPP, where no Cu deposition has been seen among the mice with less neurodegeneration [ 73 ].…”

Intravenously Injected Amyloid-β Peptide With Isomerized Asp7 and Phosphorylated Ser8 Residues Inhibits Cerebral β-Amyloidosis in AβPP/PS1 Transgenic Mice Model of Alzheimer’s Disease

“…Moreover, insights into the molecular mechanism of zinc-mediated Aβ16 oligomerization indicate that pS8-Aβ16 can form zinc-driven heterodimers with Aβ species containing the primary zinc recognition site 11EVHH14, and such heterodimers might lack the ability to oligomerize (Istrate et al, 2016; Mezentsev et al, 2016; Polshakov et al, 2017). Based on the above, we have hypothesized that incorporating phosphorylated Ser8 into isoD7-Aβ42 resulting in the peptide with both isomerized Asp7 and phosphorylated Ser8 residues (isoD7-pS8-Aβ42) could safeguard such species from zinc-induced oligomerization in vitro and in vivo .…”