Small Molecule Modulators of Copper-Induced Aβ Aggregation

Abstract

The World Health Organization estimates that ca. 11 million people worldwide have Alzheimer's disease (AD) and this population is expected to nearly double by 2030.1 This disease, which manifests in progressive neurodegeneration, is characterized by the presence of amyloid-β (Aβ) peptide aggregates.2 -4 The mechanism for the formation of Aβ aggregates is not entirely understood, though metal ions such as Cu II and Zn II have been shown to facilitate Aβ aggregation.2 -4 In particular, redox-active Cu II is implicated in the generation of reactive oxygen species (ROS), leading to an increase in oxidative stress, which is one proposed neuropathology of AD.2 -8 To elucidate Cu-mediated events in AD pathogenesis, Cu coordination to Aβ has been explored as well as effects on the removal of Cu from Cu-Aβ species using chelating agents.2 -13 These studies have demonstrated that the extent of metal-induced Aβ aggregation and ROS production can be modulated by metal chelators, which highlights metal-ion chelation therapy as a promising AD treatment.Many orthodox metal chelators show inhibition of metal-induced Aβ aggregation and ROS formation,2 -4 , 9 , 13 but they may not be suitable for AD therapeutics. Most of these chelators cannot cross the blood brain barrier (BBB) and are not able to specifically target metal ions in various Aβ forms without removing vital metals from other biological systems due to lack of an Aβ recognition ability. The metal chelator clioquinol (CQ) reveals decreased Aβ aggregate deposits and improved cognition in early clinical trials.14 The long-term use is, however, limited by an adverse side effect, subacute myelo-optic neuropathy.15 , 16 Our recent studies suggest that CQ assists, in part, in the disaggregation of Aβ aggregates, but could not completely prevent Aβ aggregation.17 Therefore, rational design of chelating agents capable of targeting metal ions in Aβ species followed by modulation of Aβ aggregation in the brain is essential toward metal-ion chelation therapy for AD. Only limited efforts have been made toward this goal.3 , 10 -12 Herein we present the preparation of bifunctional metal chelators (1 and 2) and their interaction with Cu-induced Aβ aggregates. Both chelators exhibit modulation of Cu-associated Aβ aggregation, which is more effective than that by the well-known metal chelating agents CQ, EDTA, and phen in this study.18Our strategy for developing metal chelators as potential AD therapeutics is to create bifunctional molecules that contain structural moieties for metal ion chelation and Aβ recognition (Figure 1). For the latter purpose, the basic frameworks of 1 and 2 are based on the Aβ aggregate-imaging probes 125 IMPY and p-125 I-stilbene,18 respectively, which show strong binding affinity to Aβ aggregates.19 These compounds are small, neutral, lipophilic, and thus able to penetrate the BBB. Furthermore, they are easily removed from normal brain mhlim@umich.edu . Supporting Information Available: Experimental procedures, preparation and characterization of 1 and 2, Ta...

Design of small molecules that target metal-Aβ species and regulate metal-induced Aβ aggregation and neurotoxicity

“…2) (2-4, 8, 9, 36, 37, 48). This is similar to previous results for L1, the imine based derivative of L2-b (22). This close contact of L2-b on the metal binding site of Aβ may facilitate chelation of metal ions surrounded by Aβ.…”

“…We recently reported the compound L1 that incorporates two nitrogen donor atoms into the structure of the stilbene derivative without major structural modifications ( Fig. 1) (22). Although L1 is capable of regulating metal-induced Aβ events, its biocompatibility is poor due to limited stability in water, which hinders its biological applications.…”

“…3 and Fig. S5 (inhibition: prevention of formation of metal-induced Aβ aggregates; disaggregation: transformation of metal-involved Aβ aggregates) (22). The degree of Aβ aggregation was determined by transmission electron microscopy (TEM) and native gel electrophoresis followed by Western blotting with an anti-Aβ antibody 6E10 (22).…”

“…To date, only limited efforts have been made toward this goal (2,13,(19)(20)(21)(22)(23)(24). Recently, we reported small molecules having bifunctionality (metal chelation and Aβ interaction) (22).…”

“…One of the compounds, Fig. 1), can modulate metal-induced Aβ aggregation and ROS production, leading to reduction of metal-Aβ neurotoxicity in living cells (22). Limited stability of L1 in water, however, prevents further biological applications.…”