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Reactivity of diphenylpropynone derivatives toward metal-associated amyloid-? species.

ABSTRACT: In Alzheimer's disease (AD), metal-associated amyloid-? (metal-A?) species have been suggested to be involved in neurotoxicity; however, their role in disease development is still unclear. To elucidate this aspect, chemical reagents have been developed as valuable tools for targeting metal-A? species, modulating the interaction between the metal and A?, and subsequently altering metal-A? reactivity. Herein, we report the design, preparation, characterization, and reactivity of two diphenylpropynone derivatives (DPP1 and DPP2) composed of structural moieties for metal chelation and A? interaction (bifunctionality). The interactions of these compounds with metal ions and A? species were confirmed by UV-vis, NMR, mass spectrometry, and docking studies. The effects of these bifunctional molecules on the control of in vitro metal-free and metal-induced A? aggregation were investigated and monitored by gel electrophoresis and transmission electron microscopy (TEM). Both DPP1 and DPP2 showed reactivity toward metal-A? species over metal-free A? species to different extents. In particular, DPP2, which contains a dimethylamino group, exhibited greater reactivity with metal-A? species than DPP1, suggesting a structure-reactivity relationship. Overall, our studies present a new bifunctional scaffold that could be utilized to develop chemical reagents for investigating metal-A? species in AD.

SUBMITTER: Pithadia AS

PROVIDER: S-EPMC3568435 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Reactivity of diphenylpropynone derivatives toward metal-associated amyloid-β species.

Pithadia Amit S AS Kochi Akiko A Soper Molly T MT Beck Michael W MW Liu Yuzhong Y Lee Sanghyun S DeToma Alaina S AS Ruotolo Brandon T BT Lim Mi Hee MH

Inorganic chemistry 20121115 23

In Alzheimer's disease (AD), metal-associated amyloid-β (metal-Aβ) species have been suggested to be involved in neurotoxicity; however, their role in disease development is still unclear. To elucidate this aspect, chemical reagents have been developed as valuable tools for targeting metal-Aβ species, modulating the interaction between the metal and Aβ, and subsequently altering metal-Aβ reactivity. Herein, we report the design, preparation, characterization, and reactivity of two diphenylpropyn ...[more]

PMID: 23153071

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Project description:BackgroundAlzheimer's disease (AD) is defined by amyloid beta (Aβ) plaques and neurofibrillary tangles and characterized by neurodegeneration and memory loss. The majority of AD patients also have Aβ deposition in cerebral vessels known as cerebral amyloid angiopathy (CAA), microhemorrhages, and vascular co-morbidities, suggesting that cerebrovascular dysfunction contributes to AD etiology. Promoting cerebrovascular resilience may therefore be a promising therapeutic or preventative strategy for AD. Plasma high-density lipoproteins (HDL) have several vasoprotective functions and are associated with reduced AD risk in some epidemiological studies and with reduced Aβ deposition and Aβ-induced inflammation in 3D engineered human cerebral vessels. In mice, deficiency of apoA-I, the primary protein component of HDL, increases CAA and cognitive dysfunction, whereas overexpression of apoA-I from its native promoter in liver and intestine has the opposite effect and lessens neuroinflammation. Similarly, acute peripheral administration of HDL reduces soluble Aβ pools in the brain and some studies have observed reduced CAA as well. Here, we expand upon the known effects of plasma HDL in mouse models and in vitro 3D artery models to investigate the interaction of amyloid, astrocytes, and HDL on the cerebrovasculature in APP/PS1 mice.MethodsAPP/PS1 mice deficient or hemizygous for Apoa1 were aged to 12 months. Plasma lipids, amyloid plaque deposition, Aβ protein levels, protein and mRNA markers of neuroinflammation, and astrogliosis were assessed using ELISA, qRT-PCR, and immunofluorescence. Contextual and cued fear conditioning were used to assess behavior.ResultsIn APP/PS1 mice, complete apoA-I deficiency increased total and vascular Aβ deposition in the cortex but not the hippocampus compared to APP/PS1 littermate controls hemizygous for apoA-I. Markers of both general and vascular neuroinflammation, including Il1b mRNA, ICAM-1 protein, PDGFRβ protein, and GFAP protein, were elevated in apoA-I-deficient APP/PS1 mice. Additionally, apoA-I-deficient APP/PS1 mice had elevated levels of vascular-associated ICAM-1 in the cortex and hippocampus and vascular-associated GFAP in the cortex. A striking observation was that astrocytes associated with cerebral vessels laden with Aβ or associated with Aβ plaques showed increased reactivity in APP/PS1 mice lacking apoA-I. No behavioral changes were observed.ConclusionsApoA-I-containing HDL can reduce amyloid pathology and astrocyte reactivity to parenchymal and vascular amyloid in APP/PS1 mice.

Dataset Information

Reactivity of diphenylpropynone derivatives toward metal-associated amyloid-? species.

Publications

Reactivity of diphenylpropynone derivatives toward metal-associated amyloid-β species.

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