Alzheimer’s disease (AD), the most commonly diagnosed for of dementia, affects 37 million people with no known cure, cause or early diagnosis. While there are competing ideas over AD development, one potential idea is the “metal hypothesis”, which states that metal ions (CuII, ZnII and FeII/III, AlIII) play a crucial role in AD pathogenesis. These metallated-Aβ aggregates may cause reduced cell signaling and neuronal cell death by destabilization or oxidative damage to membranes. However, depending on experimental conditions and type of Aβ aggregate, inhibitory effects are observed. For example, CuII is known to inhibit fibrillation by ZnII, while other studies show ZnII attenuates non-toxic plaque formation and is neuroprotective. Recent research has shown that soluble Aβ oligomers display more neurotoxicity than larger forms of Aβ aggregates. Understanding the relative toxicity of metallated-Aβ oligomers can aid in the understanding of how they play a part in AD progression. Consequently, controlled studies are required to uncover the important mechanisms by which metals induce Aβ oligomerization that lead to their neurotoxic or neuroprotective roles. The most convincing piece of evidence supporting a link between metal homeostasis and the two pathological processes (Ab1-42 aggregation and oxidative damage) comes from chelation studies showing resolubilization of Ab deposits and clinical improvement of patients with AD. These studies suggest that chelation therapy is a powerful “disease modifying strategy”. We will describe a new class of site-directed nanochelators to improve the limitations of traditional chelators, such as ability to cross the blood brain barrier and non-specific metal binding. The synthesis of these nanochelators and their metal binding affinities will be presented along with metal aggregation studies with Aβ using fluorescence spectroscopy.

Modulating beta amyloid (Aβ) aggregation with metal ions and nanochelators

249th National Meeting (2015)

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