Mechanistic Insights into Tunable Metal-Mediated Hydrolysis of Amyloid-β Peptides

Abstract

An amyloidogenic peptide, amyloid-β (Aβ), has been implicated as a contributor to the neurotoxicity of Alzheimer's disease (AD) that continues to present a major socioeconomic burden for our society. Recently, the use of metal complexes capable of cleaving peptides has arisen as an efficient tactic for amyloid management; unfortunately, little has been reported to pursue this strategy. Herein, we report a novel approach to validate the hydrolytic cleavage of divalent metal complexes toward two major isoforms of Aβ (Aβ and Aβ) and tune their proteolytic activity based on the choice of metal centers (M = Co, Ni, Cu, and Zn) which could be correlated to their anti-amyloidogenic properties. Such metal-dependent tunability was facilitated employing a tetra-N-methylated cyclam (TMC) ligand that imparts unique geometric and stereochemical control, which has not been available in previous systems. Co(II)(TMC) was identified to noticeably cleave Aβ peptides and control their aggregation, reporting the first Co(II) complex for such reactivities to the best of our knowledge. Through detailed mechanistic investigations by biochemical, spectroscopic, mass spectrometric, and computational studies, the critical importance of the coordination environment and acidity of the aqua-bound complexes in promoting amide hydrolysis was verified. The biological applicability of Co(II)(TMC) was also illustrated via its potential blood-brain barrier permeability, relatively low cytotoxicity, regulatory capability against toxicity induced by both Aβ and Aβ in living cells, proteolytic activity with Aβ peptides under biologically relevant conditions, and inertness toward cleavage of structured proteins. Overall, our approaches and findings on reactivities of divalent metal complexes toward Aβ, along with the mechanistic insights, demonstrate the feasibility of utilizing such metal complexes for amyloid control.

Metal–Organic Frameworks Harness Cu Chelating and Photooxidation Against Amyloid β Aggregation in Vivo

“…Therefore, inhibition of Aβ aggregation has been considered a promising approach to relieve the symptoms of AD . Most of the existing inhibitors mainly focus on a simple way to suppress Aβ aggregation, such as monomer binding, oxidizing, hydrolyzing, thermal depolymerizing, etc. Photooxygenation of Aβ has emerged as an effective way to inhibit Aβ aggregation due to the spatiotemporal controllability of light and the ability to prevent Aβ reassembly.…”

“…[1] Amyloid b (Ab)a ggregation has been regarded as the pathological hallmarko fA D, and metal ions, such as Cu, Zn, Fe, can accelerate Ab aggregation and result in neurotoxicity. [2] Therefore, inhibition of Ab aggregation has been considered a promising approach to relieve the symptomso fA D. [3] Most of the existing inhibitors mainly focuso nas imple way to suppress Ab aggregation, [4][5][6][7][8][9] such as monomer binding, oxidizing, [4] hydrolyzing, [5] thermald epolymerizing, [6] etc. Photooxygenationo fA b has emerged as an effective way to inhibitA b aggregation due to the spatiotemporal controllability of light and the ability to prevent Ab reassembly.C urrently,A b photooxidantsc an be divided into two categories:s mallm olecules [4, 10] and nanoparticles.…”

A Near‐Infrared‐Controllable Artificial Metalloprotease Used for Degrading Amyloid‐β Monomers and Aggregates

“…First of all, the hydrolytic ability of MoS 2 –Co towards Aβ 40 monomers was determined by matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry (MALDI‐TOF MS) assay . Human insulin was utilized as an internal standard to acquire quantitative information from MALDI‐TOF MS .…”

Inhibition of metal-induced amyloid β-peptide aggregation by a blood–brain barrier permeable silica–cyclen nanochelator

“…Cyclen is a metal chelator and has potential to disaggregate the metal-induced Ab aggregates as previously reported. 25,26,31 The chelating ability of SiO 2 -cyclen nanochelator was determined by ICP-MS aer incubation with Cu 2+ and Zn 2+ . The Cu and Zn amounts aer reacting with SiO 2 -cyclen were 22.18 AE 0.33 and 22.48 AE 0.29 mg mg À1 in terms of SiO 2 -cyclen weight, respectively.…”

“…24 We and other researchers ever reported that macrocyclic chelator 1,4,7,10-tetraazacyclododecane (cyclen) could reduce the metal-induced Ab aggregation and neurotoxicity. 25,26 However, the hydrophilic cyclen (water solubility: 999 g L À1 ) may be hard to cross the BBB.…”