Dataset Information

Structural and Mechanistic Insights into Development of Chemical Tools to Control Individual and Inter-Related Pathological Features in Alzheimer's Disease.

ABSTRACT: To elucidate the involvement of individual and inter-related pathological factors [i.e., amyloid-? (A?), metals, and oxidative stress] in the pathogenesis of Alzheimer's disease (AD), chemical tools have been developed. Characteristics required for such tool construction, however, have not been clearly identified; thus, the optimization of available tools or new design has been limited. Here, key structural properties and mechanisms that can determine tools' regulatory reactivities with multiple pathogenic features found in AD are reported. A series of small molecules was built up through rational structural selection and variations onto the framework of a tool useful for in vitro and in vivo metal-A? investigation. Variations include: (i)?location and number of an A? interacting moiety; (ii)?metal binding site; and (iii)?denticity and structural flexibility. Detailed biochemical, biophysical, and computational studies were able to provide a foundation of how to originate molecular formulas to devise chemical tools capable of controlling the reactivities of various pathological components through distinct mechanisms. Overall, this multidisciplinary investigation illustrates a structure-mechanism-based strategy of tool invention for such a complicated brain disease.

SUBMITTER: Lee HJ

PROVIDER: S-EPMC5826595 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Publications

Structural and Mechanistic Insights into Development of Chemical Tools to Control Individual and Inter-Related Pathological Features in Alzheimer's Disease.

Lee Hyuck Jin HJ Korshavn Kyle J KJ Nam Younwoo Y Kang Juhye J Paul Thomas J TJ Kerr Richard A RA Youn Il Seung IS Ozbil Mehmet M Kim Kwang S KS Ruotolo Brandon T BT Prabhakar Rajeev R Ramamoorthy Ayyalusamy A Lim Mi Hee MH

Chemistry (Weinheim an der Bergstrasse, Germany) 20170126 11

To elucidate the involvement of individual and inter-related pathological factors [i.e., amyloid-β (Aβ), metals, and oxidative stress] in the pathogenesis of Alzheimer's disease (AD), chemical tools have been developed. Characteristics required for such tool construction, however, have not been clearly identified; thus, the optimization of available tools or new design has been limited. Here, key structural properties and mechanisms that can determine tools' regulatory reactivities with multiple ...[more]

PMID: 28004889

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Project description:Alzheimer's disease (AD) pathologies were discovered in the accessible neurosensory retina. However, their exact nature and topographical distribution, particularly in the early stages of functional impairment, and how they relate to disease progression in the brain remain largely unknown. To better understand the pathological features of AD in the retina, we conducted an extensive histopathological and biochemical investigation of postmortem retina and brain tissues from 86 human donors. Quantitative examination of superior and inferior temporal retinas from mild cognitive impairment (MCI) and AD patients compared to those with normal cognition (NC) revealed significant increases in amyloid β-protein (Aβ42) forms and novel intraneuronal Aβ oligomers (AβOi), which were closely associated with exacerbated retinal macrogliosis, microgliosis, and tissue atrophy. These pathologies were unevenly distributed across retinal layers and geometrical areas, with the inner layers and peripheral subregions exhibiting most pronounced accumulations in the MCI and AD versus NC retinas. While microgliosis was increased in the retina of these patients, the proportion of microglial cells engaging in Aβ uptake was reduced. Female AD patients exhibited higher levels of retinal microgliosis than males. Notably, retinal Aβ42, S100 calcium-binding protein B+ macrogliosis, and atrophy correlated with severity of brain Aβ pathology, tauopathy, and atrophy, and most retinal pathologies reflected Braak staging. All retinal biomarkers correlated with the cognitive scores, with retinal Aβ42, far-peripheral AβOi and microgliosis displaying the strongest correlations. Proteomic analysis of AD retinas revealed activation of specific inflammatory and neurodegenerative processes and inhibition of oxidative phosphorylation/mitochondrial, and photoreceptor-related pathways. This study identifies and maps retinopathy in MCI and AD patients, demonstrating the quantitative relationship with brain pathology and cognition, and may lead to reliable retinal biomarkers for noninvasive retinal screening and monitoring of AD.

Dataset Information

Structural and Mechanistic Insights into Development of Chemical Tools to Control Individual and Inter-Related Pathological Features in Alzheimer's Disease.

Publications

Structural and Mechanistic Insights into Development of Chemical Tools to Control Individual and Inter-Related Pathological Features in Alzheimer's Disease.

Similar Datasets

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