scholarly journals Evaluation of Toxic Amyloid β42 Oligomers in Rat Primary Cerebral Cortex Cells and Human iPS-derived Neurons Treated with 10-Me-Aplog-1, a New PKC Activator

2020 ◽  
Vol 21 (4) ◽  
pp. 1179
Author(s):  
Kazuma Murakami ◽  
Mayuko Yoshimura ◽  
Shota Nakagawa ◽  
Toshiaki Kume ◽  
Takayuki Kondo ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Total Synthesis ◽  
Bryostatin 1 ◽  
Oligomer Formation ◽  
Promising Strategy ◽  
Secretase Activity ◽  
Drug Lead ◽  
Protein Kinase Cα ◽  
Aβ Production ◽  
Ad Therapy

Amyloid β42 (Aβ42), a causative agent of Alzheimer’s disease (AD), is derived extracellularly from Aβ precursor protein (APP) following the latter’s cleavage by β-secretase, but not α-secretase. Protein kinase Cα (PKCα) activation is known to increase α-secretase activity, thereby suppressing Aβ production. Since Aβ42 oligomer formation causes potent neurotoxicity, APP modulation by PKC ligands is a promising strategy for AD treatment. Although bryostatin-1 (bryo-1) is a leading compound for this strategy, its limited natural availability and the difficulty of its total synthesis impedes further research. To address this limitation, Irie and colleagues have developed a new PKC activator with few side effects, 10-Me-Aplog-1, (1), which decreased Aβ42 in the conditioned medium of rat primary cerebral cortex cells. These results are associated with increased α-secretase but not PKCε-dependent Aβ-degrading enzyme. The amount of neuronal embryonic lethal abnormal vision (nELAV), a known β-secretase stabilizer, was reduced by treatment with 1. Notably, 1 prevented the formation of intracellular toxic oligomers. Furthermore, 1 suppressed toxic oligomerization within human iPS-derived neurons such as bryo-1. Given that 1 was not neurotoxic toward either cell line, these findings suggest that 1 is a potential drug lead for AD therapy.

Selective Secretase Targeting for Alzheimer’s Disease Therapy

2021 ◽  
pp. 1-17
Author(s):  
Alvaro Miranda ◽  
Enrique Montiel ◽  
Henning Ulrich ◽  
Cristian Paz
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Neuroprotective Activity ◽  
Amyloid Β Protein ◽  
Secretase Activity ◽  
Membrane Bound ◽  
Aβ Production ◽  
Bace 1

Alzheimer’s disease (AD) is associated with marked atrophy of the cerebral cortex and accumulation of amyloid plaques and neurofibrillary tangles. Amyloid plaques are formed by oligomers of amyloid-β (Aβ) in the brain, with a length of 42 and 40 amino acids. α-secretase cleaves amyloid-β protein precursor (AβPP) producing the membrane-bound fragment CTFα and the soluble fragment sAβPPα with neuroprotective activity; β-secretase produces membrane-bound fragment CTFβ and a soluble fragment sAβPPβ. After α-secretase cleavage of AβPP, γ-secretase cleaves CTFα to produce the cytoplasmic fragment AICD and P3 in the non-amyloidogenic pathway. CTFβ is cleaved by γ-secretase producing AICD as well as Aβ in amyloidogenic pathways. In the last years, the study of natural products and synthetic compounds, such as α-secretase activity enhancers, β-secretase inhibitors (BACE-1), and γ-secretase activity modulators, have been the focus of pharmaceuticals and researchers. Drugs were improved regarding solubility, blood-brain barrier penetration, selectivity, and potency decreasing Aβ42. In this regard, BACE-1 inhibitors, such as Atabecestat, NB-360, Umibecestat, PF-06751979, Verubecestat, LY2886721, Lanabecestat, LY2811376, and Elenbecestat, were submitted to phase I-III clinical trials. However, inhibition of Aβ production did not recover cognitive functions or reverse the disease. Novel strategies are being developed, aiming at a partial reduction of Aβ production, such as the development of γ-secretase modulators or α-secretase enhancers. Such therapeutic tools shall focus on slowing down or minimizing the progression of neuronal damage. Here, we summarize structures and the activities of the latest compounds designed for AD treatment, with remarkable in vitro, in vivo, and clinical phase activities.

ChemInform Abstract: Total Synthesis of Bryostatin 1: A Short Route

ChemInform ◽  
2012 ◽  
Vol 43 (5) ◽  
pp. no-no
Author(s):  
Soraya Manaviazar ◽  
Karl J. Hale
Keyword(s):  
Total Synthesis ◽  
Bryostatin 1 ◽  
Short Route

scholarly journals Identification of new Presenilin-1 phosphosites: implication for γ-secretase activity and Aβ production

2015 ◽  
Vol 133 (3) ◽  
pp. 409-421 ◽  
Author(s):  
Alexandre Matz ◽  
Blanka Halamoda-Kenzaoui ◽  
Romain Hamelin ◽  
Sebastien Mosser ◽  
Jean-René Alattia ◽  
...  
Keyword(s):  
Presenilin 1 ◽  
Secretase Activity ◽  
Aβ Production

scholarly journals Neuronal Aquaporin 1 Inhibits Amyloidogenesis by Suppressing the Interaction Between Beta-Secretase and Amyloid Precursor Protein

2020 ◽  
Vol 76 (1) ◽  
pp. 23-31
Author(s):  
Jinsu Park ◽  
Meenu Madan ◽  
Srinivasulu Chigurupati ◽  
Seung Hyun Baek ◽  
Yoonsuk Cho ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Mouse Models ◽  
Cortical Neurons ◽  
Water Channel ◽  
Ectopic Expression ◽  
Amyloid Β ◽  
Human Neuroblastoma ◽  
Tissue Samples ◽  
Aquaporin 1 ◽  
Aβ Production

Abstract The accumulation of amyloid-β (Aβ) is a characteristic event in the pathogenesis of Alzheimer’s disease (AD). Aquaporin 1 (AQP1) is a membrane water channel protein belonging to the AQP family. AQP1 levels are elevated in the cerebral cortex during the early stages of AD, but the role of AQP1 in AD pathogenesis is unclear. We first determined the expression and distribution of AQP1 in brain tissue samples of AD patients and two AD mouse models (3xTg-AD and 5xFAD). AQP1 accumulation was observed in vulnerable neurons in the cerebral cortex of AD patients, and in neurons affected by the Aβ or tau pathology in the 3xTg-AD and 5xFAD mice. AQP1 levels increased in neurons as aging progressed in the AD mouse models. Stress stimuli increased AQP1 in primary cortical neurons. In response to cellular stress, AQP1 appeared to translocate to endocytic compartments of β- and γ-secretase activities. Ectopic expression of AQP1 in human neuroblastoma cells overexpressing amyloid precussir protein (APP) with the Swedish mutations reduced β-secretase (BACE1)-mediated cleavage of APP and reduced Aβ production without altering the nonamyloidogenic pathway. Conversely, knockdown of AQP1 enhanced BACE1 activity and Aβ production. Immunoprecipitation experiments showed that AQP1 decreased the association of BACE1 with APP. Analysis of a human database showed that the amount of Aβ decreases as the expression of AQP1 increases. These results suggest that the upregulation of AQP1 is an adaptive response of neurons to stress that reduces Aβ production by inhibiting the binding between BACE1 and APP.

Hydrogen Sulfide Selectively Inhibits γ-Secretase Activity and Decreases Mitochondrial Aβ Production in Neurons from APP/PS1 Transgenic Mice

2015 ◽  
Vol 41 (5) ◽  
pp. 1145-1159 ◽  
Author(s):  
Feng-li Zhao ◽  
Pei-feng Qiao ◽  
Ning Yan ◽  
Dan Gao ◽  
Meng-jie Liu ◽  
...  
Keyword(s):  
Hydrogen Sulfide ◽  
Transgenic Mice ◽  
Secretase Activity ◽  
Aβ Production

Total Synthesis of Bryostatin 1: A Short Route

2011 ◽  
Vol 50 (38) ◽  
pp. 8786-8789 ◽  
Author(s):  
Soraya Manaviazar ◽  
Karl J. Hale
Keyword(s):  
Total Synthesis ◽  
Bryostatin 1 ◽  
Short Route

scholarly journals GSAP modulates γ-secretase specificity by inducing conformational change in PS1

2018 ◽  
Author(s):  
Eitan Wong ◽  
George P. Liao ◽  
Jerry Chang ◽  
Peng Xu ◽  
Yue-Ming Li ◽  
...  
Keyword(s):  
Conformational Change ◽  
Active Site ◽  
Cultured Cells ◽  
Cross Linking ◽  
Secretase Activity ◽  
Aβ Production ◽  
Insight Into ◽  
Double Cross

AbstractThe mechanism by which GSAP (γ-secretase activating protein) regulates γ-secretase activity has not yet been elucidated. Here, we show that knockout of GSAP in cultured cells directly reduces γ-secretase activity for Aβ production, but not for Notch1 cleavage, suggesting that GSAP may induce a conformational change contributing to the specificity of γ-secretase. Furthermore, using an active site directed photoprobe with double cross-linking moieties, we demonstrate that GSAP modifies the orientation and/or distance of PS1-NTF and PS1-CTF, a region containing the active site of γ-secretase. This work offers insight into how GSAP regulates γ-secretase specificity.

scholarly journals Inhibition of Membrane Lipid-independent Protein Kinase Cα Activity by Phorbol Esters, Diacylglycerols, and Bryostatin-1

1998 ◽  
Vol 273 (36) ◽  
pp. 23160-23168 ◽  
Author(s):  
Simon J. Slater ◽  
Frank J. Taddeo ◽  
Anthony Mazurek ◽  
Brigid A. Stagliano ◽  
Shawn K. Milano ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Phorbol Esters ◽  
Membrane Lipid ◽  
Bryostatin 1 ◽  
Protein Kinase Cα ◽  
Independent Protein

SERP1 is an assembly regulator of γ-secretase in metabolic stress conditions

2020 ◽  
Vol 13 (623) ◽  
pp. eaax8949 ◽  
Author(s):  
Sunmin Jung ◽  
Junho Hyun ◽  
Jihoon Nah ◽  
Jonghee Han ◽  
Seo-Hyun Kim ◽  
...  
Keyword(s):  
Er Stress ◽  
Parietal Lobe ◽  
Metabolic Stress ◽  
Expression Library ◽  
Genome Wide ◽  
Secretase Activity ◽  
A Genome ◽  
Aβ Generation ◽  
Aβ Production ◽  
In Cells

The enzyme γ-secretase generates β-amyloid (Aβ) peptides by cleaving amyloid protein precursor (APP); the aggregation of these peptides is associated with Alzheimer’s disease (AD). Despite the development of various γ-secretase regulators, their clinical use is limited by coincident disruption of other γ-secretase–regulated substrates, such as Notch. Using a genome-wide functional screen of γ-secretase activity in cells and a complementary DNA expression library, we found that SERP1 is a previously unknown γ-secretase activator that stimulates Aβ generation in cells experiencing endoplasmic reticulum (ER) stress, such as is seen with diabetes. SERP1 interacted with a subcomplex of γ-secretase (APH1A/NCT) through its carboxyl terminus to enhance the assembly and, consequently, the activity of the γ-secretase holoenzyme complex. In response to ER stress, SERP1 preferentially recruited APP rather than Notch into the γ-secretase complex and enhanced the subcellular localization of the complex into lipid rafts, increasing Aβ production. Moreover, SERP1 abundance, γ-secretase assembly, and Aβ production were increased both in cells exposed to high amounts of glucose and in diabetic AD model mice. Conversely, Aβ production was decreased by knocking down SERP1 in cells or in the hippocampi of mice. Compared to postmortem samples from control individuals, those from patients with AD showed increased SERP1 expression in the hippocampus and parietal lobe. Together, our findings suggest that SERP1 is an APP-biased regulator of γ-secretase function in the context of cell stress, providing a possible molecular explanation for the link between diabetes and sporadic AD.

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