scholarly journals Discovery of aryl aminothiazole γ-secretase modulators with novel effects on amyloid β-peptide production

2021 ◽  
Author(s):  
Sanjay Bhattarai ◽  
Lei Liu ◽  
Michael S Wolfe
Keyword(s):  
Structural Changes ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
Mechanistic Studies ◽  
Parent Molecule ◽  
Aβ Peptides ◽  
Protein Substrate ◽  
New Compounds ◽  
Aβ Production

A series of analogs based on a prototype aryl aminothiazole γ-secretase modulator (GSM) were synthesized and tested for their effects on the profile of 37-to-42-residue amyloid β-peptides (Aβ) generated through processive proteolysis of precursor protein substrate by γ-secretase. Certain substitutions on the terminal aryl D ring resulted in an altered profile of Aβ production compared to that seen with the parent molecule. Small structural changes led to concentration-dependent increases in Aβ37 and Aβ38 production without parallel decreases in their precursors Aβ40 and Aβ42, respectively. The new compounds therefore apparently also stimulate carboxypeptidase trimming of Aβ peptides > 43 residues, providing novel chemical tools for mechanistic studies of processive proteolysis by γ-secretase.

Cholesterol and Alzheimer's disease

2002 ◽  
Vol 30 (4) ◽  
pp. 525-529 ◽  
Author(s):  
B. Wolozin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Hmg Coa Reductase ◽  
Production Studies ◽  
Amino Acid Peptide ◽  
Reductase Inhibitors ◽  
Coa Reductase ◽  
Aβ Production

Accumulation of a 40–42-amino acid peptide, termed amyloid-β peptide (Aβ), is associated with Alzheimer's disease (AD), and identifying medicines that inhibit Aβ could help patients with AD. Recent evidence suggests that a class of medicines that lower cholesterol by blocking the enzyme 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase), termed statins, can inhibit Aβ production. Increasing evidence suggests that the enzymes that generate Aβ function best in a high-cholesterol environment, which might explain why reducing cholesterol would inhibit Aβ production. Studies using both neurons and peripheral cells show that reducing cellular cholesterol levels, by stripping off the cholesterol with methyl-β-cyclodextrin or by treating the cells with HMG-CoA reductase inhibitors, decreases Aβ production. Studies performed on animal models and on humans concur with these results. In humans, lovastatin, an HMG-CoA reductase inhibitor, has been shown to reduce Aβ levels in blood of patients by up to 40%. The putative role of Aβ in AD raises the possibility that treating patients with statins might lower Aβ, and thereby either delay the occurrence of AD or retard the progression of AD. Two large retrospective studies support this hypothesis. Both studies suggest that patients taking statins had an approx. 70% lower risk of developing AD. Since statins are widely used by doctors, their ability to reduce Aβ offers a putative therapeutic strategy for treating AD by using medicines that have already been proved safe to use in humans.

A theoretical study on the molecular determinants of the affibody protein ZAβ3bound to an amyloid β peptide

2015 ◽  
Vol 17 (26) ◽  
pp. 16886-16893 ◽  
Author(s):  
Xu Wang ◽  
Xianqiang Sun ◽  
Guanglin Kuang ◽  
Hans Ågren ◽  
Yaoquan Tu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Theoretical Study ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Aβ Peptides ◽  
Molecular Determinants

The investigation of the (ZAβ3)2:Aβ complex highlights the energetic contribution of affibody residues to the binding with alzheimer's disease associated Aβ peptides.

scholarly journals Amyloid-β Peptide Exacerbates the Memory Deficit Caused by Amyloid Precursor Protein Loss-of-Function in Drosophila

PLoS ONE ◽  
2015 ◽  
Vol 10 (8) ◽  
pp. e0135741 ◽  
Author(s):  
Isabelle Bourdet ◽  
Aurélie Lampin-Saint-Amaux ◽  
Thomas Preat ◽  
Valérie Goguel
Keyword(s):  
Amyloid Precursor Protein ◽  
Amyloid Β ◽  
Memory Deficit ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
Loss Of Function ◽  
Protein Loss

scholarly journals Zinc and Copper Differentially Modulate Amyloid Precursor Protein Processing by γ-Secretase and Amyloid-β Peptide Production

2017 ◽  
Vol 292 (9) ◽  
pp. 3751-3767 ◽  
Author(s):  
Hermeto Gerber ◽  
Fang Wu ◽  
Mitko Dimitrov ◽  
Guillermo M. Garcia Osuna ◽  
Patrick C. Fraering
Keyword(s):  
Amyloid Precursor Protein ◽  
Amyloid Β ◽  
Protein Processing ◽  
Precursor Protein ◽  
Amyloid Precursor Protein Processing ◽  
Amyloid Β Peptide

scholarly journals Implication of exosomes derived from cholesterol-accumulated astrocytes in Alzheimer's disease pathology

2021 ◽  
Author(s):  
Qi Wu ◽  
Leonardo Cortez ◽  
Razieh Kamali-Jamil ◽  
Valerie Sim ◽  
Holger Wille ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Influence Function ◽  
Critical Role ◽  
Amyloid Β ◽  
Cholesterol Accumulation ◽  
Aβ Peptides ◽  
Neuronal Viability ◽  
Cultured Astrocytes ◽  
Aβ Production

Amyloid β (Aβ) peptides generated from the amyloid precursor protein (APP) play a critical role in the development of Alzheimer's disease (AD) pathology. Aβ-containing neuronal exosomes, which represent a novel form of intercellular communication, have been shown to influence function/vulnerability of neurons in AD. Unlike neurons, the significance of exosomes derived from astrocytes remains unclear. In this study, we evaluated the significance of exosomes derived from U18666A-induced cholesterol-accumulated astrocytes in the development of AD pathology. Our results show that cholesterol accumulation decreases exosome secretion, whereas lowering cholesterol level increases exosome secretion from cultured astrocytes. Interestingly, exosomes secreted from U18666A-treated astrocytes contain higher levels of APP, APP-CTFs, soluble APP, APP secretases and Aβ1-40 than exosomes secreted from control astrocytes. Furthermore, we show that exosomes derived from U18666A-treated astrocytes can lead to neurodegeneration, which is attenuated by decreasing Aβ production or by neutralizing exosomal Aβ peptide with an Aβ antibody. These results, taken together, suggest that exosomes derived from cholesterol-accumulated astrocytes can play an important role in trafficking APP/Aβ peptides and influencing neuronal viability in the affected regions of the AD brain.

scholarly journals Inhibition of Glycosphingolipid Biosynthesis Reduces Secretion of the β-Amyloid Precursor Protein and Amyloid β-Peptide

2005 ◽  
Vol 280 (30) ◽  
pp. 28110-28117 ◽  
Author(s):  
Irfan Y. Tamboli ◽  
Kai Prager ◽  
Esther Barth ◽  
Michael Heneka ◽  
Konrad Sandhoff ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
Β Amyloid ◽  
Glycosphingolipid Biosynthesis

scholarly journals COPS5 (Jab1) Protein Increases β Site Processing of Amyloid Precursor Protein and Amyloid β Peptide Generation by Stabilizing RanBP9 Protein Levels

2013 ◽  
Vol 288 (37) ◽  
pp. 26668-26677 ◽  
Author(s):  
Hongjie Wang ◽  
Debleena Dey ◽  
Ivan Carrera ◽  
Dmitriy Minond ◽  
Elisabetta Bianchi ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
Protein Levels

The novel β-secretase inhibitor KMI-429 reduces amyloid β peptide production in amyloid precursor protein transgenic and wild-type mice

2006 ◽  
Vol 96 (2) ◽  
pp. 533-540 ◽  
Author(s):  
Masashi Asai ◽  
Chinatsu Hattori ◽  
Nobuhisa Iwata ◽  
Takaomi C. Saido ◽  
Noboru Sasagawa ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
The Novel ◽  
Wild Type ◽  
Secretase Inhibitor

scholarly journals Sp1 and Smad transcription factors co-operate to mediate TGF-β-dependent activation of amyloid-β precursor protein gene transcription

2004 ◽  
Vol 383 (2) ◽  
pp. 393-399 ◽  
Author(s):  
Fabian DOCAGNE ◽  
Cecilia GABRIEL ◽  
Nathalie LEBEURRIER ◽  
Sylvain LESNÉ ◽  
Yannick HOMMET ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcriptional Activity ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Amyloid Β ◽  
Transforming Growth Factor Β ◽  
Precursor Protein ◽  
Transcriptional Level ◽  
Amyloid Β Peptide ◽  
Aβ Amyloid

Abnormal deposition of Aβ (amyloid-β peptide) is one of the hallmarks of AD (Alzheimer's disease). This peptide results from the processing and cleavage of its precursor protein, APP (amyloid-β precursor protein). We have demonstrated previously that TGF-β (transforming growth factor-β), which is overexpressed in AD patients, is capable of enhancing the synthesis of APP by astrocytes by a transcriptional mechanism leading to the accumulation of Aβ. In the present study, we aimed at further characterization of the molecular mechanisms sustaining this TGF-β-dependent transcriptional activity. We report the following findings: first, TGF-β is capable of inducing the transcriptional activity of a reporter gene construct corresponding to the +54/+74 region of the APP promoter, named APPTRE (APP TGF-β-responsive element); secondly, although this effect is mediated by a transduction pathway involving Smad3 (signalling mother against decapentaplegic peptide 3) and Smad4, Smad2 or other Smads failed to induce the activity of APPTRE. We also observed that the APPTRE sequence not only responds to the Smad3 transcription factor, but also the Sp1 (signal protein 1) transcription factor co-operates with Smads to potentiate the TGF-β-dependent activation of APP. TGF-β signalling induces the formation of nuclear complexes composed of Sp1, Smad3 and Smad4. Overall, the present study gives new insights for a better understanding of the fine molecular mechanisms occurring at the transcriptional level and regulating TGF-β-dependent transcription. In the context of AD, our results provide additional evidence for a key role for TGF-β in the regulation of Aβ production.

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