Development of Small Molecules to Target and Modulate Multiple Factors in the Neuropathogenesis of Alzheimer's Disease.

[摘要] Alzheimer’s disease (AD) is one of the leading cause of death; being the only cause to have increased attribution to death necessitates the understanding of its etiology. Several pathological features, including accumulation of misfolded proteins (i.e., amyloid-β; Aβ), metal ion dyshomeostasis, and loss of acetylcholine (ACh) neurotransmission, are suggested in AD pathogenesis. Current AD therapeutics focus on inhibition of acetylcholinesterase (AChE) for mitigating ACh breakdown. Extensive studies indicate a potential interconnection between Aβ and metal ions (i.e., Cu2+/Zn2+) as well as between Aβ and AChE. Aforementioned factors or their inter-relationships in neuropathogenesis are unclear, however. To understand the correlation between these factors, efforts have been made toward the development of small molecules as chemical tools, capable of targeting them and subsequently regulating their reactivity.For such purposes, in this thesis, diphenylpropynone (DPP; Aβ imaging probe) derivatives, bioapplicable molecules (i.e., curcumin, in curry and enediyne, framework used in cancer research), as well as a multifunctional hybrid molecule (hybrid 5) were developed and investigated toward their targets. DPP derivatives are observed to interact with Aβ species and metal ions. The bifunctionality (Aβ interaction and metal chelation) of these derivatives is able to influence the reactivity (metal-induced Aβ aggregation) of metal-associated Aβ (metal–Aβ) species in vitro. The GdIIIDTPA-curcumin conjugate, a synthesized, Aβ specific MRI agent, is also found to target metal–Aβ species and modulate metal-triggered Aβ aggregation. This study presents the potential to develop a theranostic (diagnostic and therapeutic) agent all-in-one. The enediyne derivative, with its proclivity to generate radicals, is shown to target metal–Aβ species and control the Aβ aggregation possibly via multiple properties (i.e., metal chelation, Aβ interaction, radical generation). Lastly, hybrid 5 interacts with various targets (Aβ, metals, and AChE), is able to inhibit AChE activity with and without Aβ and metals, and modulate metal-induced Aβ aggregation in the absence and presence of AChE. Through this finding, the feasibility of designing a single molecule for multiple functions was indicated. Taken together, the presented studies demonstrate the development of small molecules as chemical tools that can be used to understand the involvement of multiple factors in AD pathogenesis.

[发布机构] University of Michigan

[效力级别] Chemistry

[关键词] Development of Small Molecules to Target and Modulate Multiple Facets of AD Neuropathogenesis;Chemistry;Science;Chemistry