Small Molecule Structure Correctors Abolish Detrimental Effects of Apolipoprotein E4 in Cultured Neurons

Chen, Hung-Kai; Liu, Zhaoping; Meyer-Franke, Anke; Brodbeck, Jens; Miranda, R. Dennis; McGuire, Joseph; Pleiss, Michael A.; Zhong, Jingxiang; Balestra, Maureen E.; Walker, David W.; Xu, Qin; Jeong, Dah Eun; Budamagunta, Madhu S.; Voss, John C.; Freedman, Stephen B.; Weisgraber, Karl H.; Huang, Yadong; Mahley, Robert W.

doi:10.1074/jbc.m111.276162

Cited by 124 publications

(154 citation statements)

References 81 publications

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“…Because abnormal macrophage functions and inflammation are important contributors to a wide spectrum of metabolic diseases, including atherosclerosis, diabetes, and Alzheimer disease, the association between apoE4 with the same spectrum of metabolic diseases may be due in large part to its role in promoting macrophage dysfunction. Moreover, apoE4 structure correctors that have been proposed for Alzheimer disease modulation (57,58) may also be tested for efficacy in reducing the risk of atherosclerosis, diabetes, and other inflammatory diseases associated with the ⑀4 genotype.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E4 Impairs Macrophage Efferocytosis and Potentiates Apoptosis by Accelerating Endoplasmic Reticulum Stress

Cash

Kuhel

Basford

et al. 2012

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Apolipoprotein E4 Impairs Macrophage Efferocytosis and Potentiates Apoptosis by Accelerating Endoplasmic Reticulum Stress

Cash

Kuhel

Basford

et al. 2012

Journal of Biological Chemistry

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“…Overall, the current findings suggest that the pathological effects associated with apoE4 may be offset by treatments that enhance its tetramer-forming ability to that of apoE3. It is possible that smallmolecule "structure correctors" that bind to apoE4 and make it behave more like apoE3 (49,50) work in this fashion.…”

Section: Influence Of Differences In Secondary Structure On Apoe3 Andmentioning

confidence: 99%

Helical structure, stability, and dynamics in human apolipoprotein E3 and E4 by hydrogen exchange and mass spectrometry

Chetty

Mayne

Lund‐Katz

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Apolipoprotein E (apoE) plays a critical role in cholesterol transport in both peripheral circulation and brain. Human apoE is a polymorphic 299-residue protein in which the less common E4 isoform differs from the major E3 isoform only by a C112R substitution. ApoE4 interacts with lipoprotein particles and with the amyloid-β peptide, and it is associated with increased incidence of cardiovascular and Alzheimer's disease. To understand the structural basis for the differences between apoE3 and E4 functionality, we used hydrogen−deuterium exchange coupled with a fragment separation method and mass spectrometric analysis to compare their secondary structures at near amino acid resolution. We determined the positions, dynamics, and stabilities of the helical segments in these two proteins, in their normal tetrameric state and in mutation-induced monomeric mutants. Consistent with prior X-ray crystallography and NMR results, the N-terminal domain contains four α-helices, 20 to 30 amino acids long. The C-terminal domain is relatively unstructured in the monomeric state but forms an α-helix ∼70 residues long in the self-associated tetrameric state. Helix stabilities are relatively low, 4 kcal/mol to 5 kcal/mol, consistent with flexibility and facile reversible unfolding. Secondary structure in the tetrameric apoE3 and E4 isoforms is similar except that some helical segments in apoE4 spanning residues 12 to 20 and 204 to 210 are unfolded. These conformational differences result from the C112R substitution in the N-terminal helix bundle and likely relate to a reduced ability of apoE4 to form tetramers, thereby increasing the concentration of functional apoE4 monomers, which gives rise to its higher lipid binding compared with apoE3.apolipoprotein E | hydrogen exchange mass spectrometry | cholesterol | protein secondary structure | amphipathic helix

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“…A small number of studies have attempted to conduct phenotypic screening relevant to AD, mainly by examining amyloid precursor protein (APP) and APP metabolites, including amyloid β-peptide (Aβ), using libraries of a few hundred Food and Drug Administration (FDA)-approved drugs in neuronal cell lines [22][23][24]. Recently, screening has been conducted to identify compounds that can modulate additional AD-associated phenotypes such as Aβ-induced cytotoxicity, tau protein levels, apolipoprotein E (apoE) secretion or apoE4 conformation, Ca 2+ signaling and neurogenesis in neuronal cell lines [22,[25][26][27][28][29][30]. Within industry-sponsored phenotypic screening initiatives, apoE stimulators for possible AD therapeutics have been pursued by Eli Lilly's Phenotypic Drug Discovery Initiative (PD2) [31].…”

Section: Phenotypic Approachesmentioning

confidence: 99%

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

Kim

2015

Neurotherapeutics

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Summary Alzheimer's disease (AD) is the most common cause of dementia and represents one of the highest unmet needs in medicine today. Drug development efforts for AD have been encumbered by largely unsuccessful clinical trials in the last decade. Drug repositioning, a process of discovering a new therapeutic use for existing drugs or drug candidates, is an attractive and timely drug development strategy especially for AD. Compared with traditional de novo drug development, time and cost are reduced as the safety and pharmacokinetic properties of most repositioning candidates have already been determined. A majority of drug repositioning efforts for AD have been based on positive clinical or epidemiological observations or in vivo efficacy found in mouse models of AD. More systematic, multidisciplinary approaches will further facilitate drug repositioning for AD. Some experimental approaches include unbiased phenotypic screening using the library of available drug collections in physiologically relevant model systems (e.g. stem cell-derived neurons or glial cells), computational prediction and selection approaches that leverage the accumulating data resulting from RNA expression profiles, and genome-wide association studies. This review will summarize several notable strategies and representative examples of drug repositioning for AD.

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Small Molecule Structure Correctors Abolish Detrimental Effects of Apolipoprotein E4 in Cultured Neurons

Cited by 124 publications

References 81 publications

Apolipoprotein E4 Impairs Macrophage Efferocytosis and Potentiates Apoptosis by Accelerating Endoplasmic Reticulum Stress

Apolipoprotein E4 Impairs Macrophage Efferocytosis and Potentiates Apoptosis by Accelerating Endoplasmic Reticulum Stress

Helical structure, stability, and dynamics in human apolipoprotein E3 and E4 by hydrogen exchange and mass spectrometry

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

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