Nanoparticle–chelator conjugates as inhibitors of amyloid-β aggregation and neurotoxicity: A novel therapeutic approach for Alzheimer disease

Abstract

Oxidative stress and amyloid-β are considered major etiological and pathological factors in the initiation and promotion of neurodegeneration in Alzheimer disease (AD). Insomuch as causes of such oxidative stress, transition metals, such as iron and copper, which are found in high concentrations in the brains of AD patients and accumulate specifically in the pathological lesions, are viewed as key contributors to the altered redox state. Likewise, the aggregation and toxicity of amyloid-β is dependent upon transition metals. As such, chelating agents that selectively bind to and remove and/or "redox silence" transition metals have long been considered an attractive therapeutic target for AD. However, the blood-brain barrier and neurotoxicity of many traditional metal chelators has limited their utility in AD or other neurodegenerative disorders. To circumvent this, we previously suggested that nanoparticles conjugated to iron chelators may have the potential to deliver chelators into the brain and overcome such issues as chelator bioavailability and toxic side-effects. In this study, we synthesized a prototype nanoparticle-chelator conjugate (Nano-N2PY) and demonstrated its ability to protect human cortical neurons from amyloid-β-associated oxidative toxicity. Furthermore, Nano-N2PY nanoparticle-chelator conjugates effectively inhibited amyloid-β aggregate formation. Overall, this study indicates that Nano-N2PY, or other nanoparticles conjugated to metal chelators, may provide a novel therapeutic strategy for AD and other neurodegenerative diseases associated with excess transition metals.

Especiação de cobre e zinco em urina: importância dos metais em doenças neurodegenerativas

“…24 Suspeita-se que a secreção e a deposição do βA, bem como a agregação das placas senis ocorrem num segundo plano, funcionando como uma tentativa das células se protegerem contra os danos provocados pelo stress oxidativo. 25 Biometais como o cobre (Cu) e o zinco (Zn) circulam no cére-bro de forma regulada, através da barreira hematoencefálica. O Cu encontra-se distribuído por todo o organismo preferencialmente na forma de complexo orgânico, normalmente associado a metaloproteínas com função enzimática.…”

Therapeutic targets of brain insulin resistance in sporadic Alzheimer s disease

“…Another approach may be to conjugate chelators to nanoparticles that can cross the blood-brain barrier to chelate metal ions, and then exit to remove them (261)(262)(263). Recently, Nano-N2PY, a prototype nanoparticle-chelator conjugate was demonstrated to inhibit AβPP-Aβ aggregation and reduce AβPP-Aβ-associated cortical neuron toxicity in vivo (264). Another novel approach involved the development of site-activated multifunctional chelators, such as HLA20A, that become activated by binding and inhibiting acetylcholinesterase, resulting in the release of an active chelator that reduces AβPP-Aβ fibrillization and oxidative stress (265,266).…”

Nanotechnology for Alzheimer’s disease detection and treatment

“…Later, Liu et al suggested another synthesized nanoparticle-chelator conjugate (named Nano-N2PY), and demonstrated its in vitro ability to inhibit the cytotoxic effects of Aβ on human cortical neurons [81]. The nanoparticles used in this study were made of carboxyl functionalized polystyrene.…”

“…In addition, such a nanoparticle conjugate is capable of transporting metal chelators across the BBB, without disrupting the metal binding feature of the chelator. In addition to increasing the efficacy of metal chelating strategy, these nanoparticle conjugates were shown to reduce the toxicity of chelation strategy, by decreasing the lipophilicity of the chelators [81].…”