377 results on '"Amyloid peptide"'
Search Results
2. Antioxidant properties of Trifolium resupinatum and its therapeutic potential for Alzheimer's disease.
- Author
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Mardi, Shayan, Salemi, Zahra, and Palizvan, Mohammad-Reza
- Abstract
Introduction: Alzheimer's disease (AD) is the most common cause of dementia and is characterized by a progressive deterioration in cognitive function, which typically begins with impairment in memory. Persian clover (Trifolium resupinatum) is an annual plant found in central Asia. Due to its contents (high flavonoid and isoflavones), extensive researches have been done on its therapeutic properties, such as multiple sclerosis (MS) treatment. In this study, we investigate the neuroprotective effects of this plant on Streptozotocin (STZ)-induced AD in rats. Material and methods: This research aimed to evaluate the neuroprotective effect of Trifolium resupinatum on the spatial learning and memory, superoxide dismutase (SOD), expressions of ß amyloid 1-42 (Aß1-42), and ß amyloid 1-40 (Aß1-40) in the hippocampus of STZ-induced Alzheimer rats. Results: Our data showed that Trifolium resupinatum extract administration for two weeks before and one week after AD induction significantly improves maze escape latency (p = 0.027, 0.001 and 0.02 in 100, 200, and 300 mg of the extract, respectively) and maze retention time (p = 0.003, 0.04 and 0.001 in 100, 200, and 300 mg of the extract, respectively). Also, the administration of this extract significantly increases the SOD levels from 1.72+0.20 to 2.31+0.45 (p = 0.009), 2.48+0.32 (p = 0.001) and 2.33+0.32 (p = 0.007) and decreases the expressions of Aß1-42) (p = 0.001 in all concentrations of the extract) and Aß1-40) (p = 0.001 in all concentrations of the extract) in the rat's hippocampus. Conclusions: This study suggests that the alcoholic extract of Trifolium resupinatum has anti-Alzheimer and neuroprotective effects on rats. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
3. MT5-MMP promotes neuroinflammation, neuronal excitability and Aβ production in primary neuron/astrocyte cultures from the 5xFAD mouse model of Alzheimer’s disease
- Author
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Dominika Pilat, Jean-Michel Paumier, Laura García-González, Laurence Louis, Delphine Stephan, Christine Manrique, Michel Khrestchatisky, Eric Di Pasquale, Kévin Baranger, and Santiago Rivera
- Subjects
Neuroinflammation ,IL-1β ,Amyloid peptide ,Amyloid precursor protein ,C99 ,Synaptic activity ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background Membrane-type matrix metalloproteinase 5 (MT5-MMP) deficiency in the 5xFAD mouse model of Alzheimer's disease (AD) reduces brain neuroinflammation and amyloidosis, and prevents deficits in synaptic activity and cognition in prodromal stages of the disease. In addition, MT5-MMP deficiency prevents interleukin-1 beta (IL-1β)-mediated inflammation in the peripheral nervous system. In this context, we hypothesized that the MT5-MMP/IL-1β tandem could regulate nascent AD pathogenic events in developing neural cells shortly after the onset of transgene activation. Methods To test this hypothesis, we used 11–14 day in vitro primary cortical cultures from wild type, MT5-MMP−/−, 5xFAD and 5xFAD/MT5-MMP−/− mice, and evaluated the impact of MT5-MMP deficiency and IL-1β treatment for 24 h, by performing whole cell patch-clamp recordings, RT-qPCR, western blot, gel zymography, ELISA, immunocytochemistry and adeno-associated virus (AAV)-mediated transduction. Results 5xFAD cells showed higher levels of MT5-MMP than wild type, concomitant with higher basal levels of inflammatory mediators. Moreover, MT5-MMP-deficient cultures had strong decrease of the inflammatory response to IL-1β, as well as decreased stability of recombinant IL-1β. The levels of amyloid beta peptide (Aβ) were similar in 5xFAD and wild-type cultures, and IL-1β treatment did not affect Aβ levels. Instead, the absence of MT5-MMP significantly reduced Aβ by more than 40% while sparing APP metabolism, suggesting altogether no functional crosstalk between IL-1β and APP/Aβ, as well as independent control of their levels by MT5-MMP. The lack of MT5-MMP strongly downregulated the AAV-induced neuronal accumulation of the C-terminal APP fragment, C99, and subsequently that of Aβ. Finally, MT5-MMP deficiency prevented basal hyperexcitability observed in 5xFAD neurons, but not hyperexcitability induced by IL-1β treatment. Conclusions Neuroinflammation and hyperexcitability precede Aβ accumulation in developing neural cells with nascent expression of AD transgenes. MT5-MMP deletion is able to tune down basal neuronal inflammation and hyperexcitability, as well as APP/Aβ metabolism. In addition, MT5-MMP deficiency prevents IL-1β-mediated effects in brain cells, except hyperexcitability. Overall, this work reinforces the idea that MT5-MMP is at the crossroads of pathogenic AD pathways that are already incipiently activated in developing neural cells, and that targeting MT5-MMP opens interesting therapeutic prospects.
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- 2022
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4. Morphofunctional Changes in the Brain Nervous Tissue of 5xFAD Transgenic Mice.
- Author
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Tumanova, N. L., Vasiliev, D. S., Dubrovskaya, N. M., and Nalivaeva, N. N.
- Abstract
In the present study, in modeling the pathogenesis of Alzheimer's disease in 5xFAD transgenic mice, a comparative analysis of structural and ultrastructural changes in the nervous tissue of the olfactory bulbs, hippocampus, and entorhinal cortex was performed; in addition, the distribution of the main amyloid-degrading neuropeptidase, neprilysin (NEP), relative to wild-type mice was examined. The investigation of the structure of the nervous tissue showed that the death of brain neurons increased in transgenic animals characterized by increased production of the amyloid peptide Aβ. As a result, connections between neurons were interrupted and the neural network become disrupted. Our electron-microscopy examination revealed a reduced density of synaptic contacts and dendritic spines, local lesions of the nervous tissue, and the appearance of autophagolysosomes in the neuropil tissue of these structures in 5xFAD mice. Signs indicating increased neurodegenerative processes compared with wild-type mice were visible. In 5xFAD mice, the distribution of amyloid-degrading peptidase NEP in the entorhinal cortex and hippocampus was altered, and there was a decreased intensity of its staining in the entorhinal cortex. In transgenic mice aged 6 months, memory impairment was observed in the recognition test of new objects relative to wild-type mice. [ABSTRACT FROM AUTHOR]
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- 2022
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5. ROF-2 as an Aggregation-Induced Emission (AIE) Probe for Multi-Target Amyloid Detection and Screening of Amyloid Inhibitors.
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Tang Y, Zhang D, and Zheng J
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- Humans, Protein Aggregates drug effects, Animals, Islet Amyloid Polypeptide metabolism, Islet Amyloid Polypeptide chemistry, Amyloid beta-Peptides antagonists & inhibitors, Amyloid beta-Peptides metabolism, Amyloid metabolism, Amyloid antagonists & inhibitors
- Abstract
Misfolding and aggregation of amyloid peptides into β-structure-rich fibrils represent pivotal pathological features in various neurodegenerative diseases, including Alzheimer's disease (AD), type II diabetes (T2D), and medullary thyroid carcinoma (MTC). The development of effective amyloid detectors and inhibitors for probing and preventing amyloid aggregation is crucial for diagnosing and treating debilitating diseases, yet it poses significant challenges. Here, an aggregation-induced emission (AIE) molecule of ROF2 with multifaceted functionalities as an amyloid probe and a screening tool for amyloid inhibitors using different biophysical, cellular, and worm assays, are reported. As an amyloid probe, ROF2 outperformed ThT, demonstrating its superior sensing capability in monitoring, detecting, and distinguishing amyloid aggregates of different sequences (Amyloid-β, human islet amyloid polypeptide, or human calcitonin) and sizes (monomers, oligomers, or fibrils). More importantly, the utilization of ROF2 as a screening molecule to identify and repurpose cardiovascular drugs as amyloid inhibitors is introduced. These drugs exhibit potent amyloid inhibition properties, effectively preventing amyloid aggregation and reducing amyloid-induced cytotoxicity both in cells and nematode. The findings present a novel strategy to discovery AIE-based amyloid probes and to be used to repurpose amyloid inhibitors, expanding diagnostic and therapeutic options for neurodegenerative diseases while addressing vascular congestion and amyloid aggregation risks., (© 2024 Wiley‐VCH GmbH.)
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- 2024
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6. Molecular Docking of Compounds Modulating Amyloid Peptide Aggregation Schemes
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Ginosyan, S., Hambardzumyan, Y., Mkrtchyan, T., Grabski, H., Tiratsuyan, S., Magjarevic, Ratko, Series Editor, Ładyżyński, Piotr, Associate Editor, Ibrahim, Fatimah, Associate Editor, Lackovic, Igor, Associate Editor, Rock, Emilio Sacristan, Associate Editor, Tiginyanu, Ion, editor, Sontea, Victor, editor, and Railean, Serghei, editor
- Published
- 2020
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7. Editorial: Oligomerization and fibrillation of amyloid peptides: Mechanism, toxicity and inhibition
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Zhenyu Qian, Nabanita Saikia, and Yunxiang Sun
- Subjects
Amyloid peptide ,protein aggregation ,protein-nanoparticle interaction ,protein-membrane interaction ,inhibitory mechanism ,Biology (General) ,QH301-705.5 - Published
- 2022
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8. Neurodegenerative Changes in the Structural and Ultrastructural Organization in the Pyriform Cortex of 5xFAD Transgenic Mice.
- Author
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Tumanova, N. L., Vasilev, D. S., Dubrovskaya, N. M., and Nalivaeva, N. N.
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ENTORHINAL cortex , *TRANSGENIC mice , *MYELIN proteins , *OLFACTORY receptors , *SYNAPTIC vesicles , *PATHOLOGICAL physiology , *ALZHEIMER'S disease , *PEPTIDES - Abstract
Analysis of pathological changes in the structural and functional organization of the pyriform cortex in mice of the 5xFAD line, which models the pathogenesis of Alzheimer's disease, showed that at the age of 7 months there is an increased aggregation of β-amyloid peptide, neuronal death, disintegration of myelin sheaths of nerve fibers, agglutination of synaptic vesicles in synaptic endings and the appearance of a large number of autophagolysosomes in the bodies and processes of neurons. Also, in the pyriform cortex of such animals, foci of gliosis and an almost threefold increase in the content of the glial marker protein GFAP compared with wild type animals were found. All these changes were more pronounced than in the entorhinal cortex of 5xFAD mice that we had previously studied. Between the pyriform and entorhinal regions, a difference in the distribution of the amyloid-degrading metallopeptidase neprilysin (NEP) was also revealed. In the pyriform cortex, this enzyme is found mainly in the intercellular space, whereas in the entorhinal cortex, in the cell bodies. Moreover, in the entorhinal cortex of 5xFAD mice, the number of NEP-positive cells was 60% lower than in wild-type mice. 5xFAD mice also showed a significant deterioration in olfactory function, which was expressed in an almost twofold decrease in the effectiveness of the search for food by smell compared to wild-type mice. These findings suggest significant pathological changes in the pyriform and entorhinal cortex in 5xFAD mice caused by amyloid accumulation, which may cause a deterioration in their sense of smell, and similarly might cause impaired olfactory function in the development of Alzheimer's disease. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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9. Synthesis and biological study of new galanthamine-peptide derivatives designed for prevention and treatment of Alzheimer's disease.
- Author
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Vezenkov, Lyubomir T., Danalev, Dancho L., Iwanov, Iwan, Lozanov, Valentin, Atanasov, Atanas, Todorova, Rumyana, Vassilev, Nikolay, and Karadjova, Veronika
- Subjects
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BIOSYNTHESIS , *THERAPEUTICS , *ALZHEIMER'S disease , *PLATELET-rich plasma , *BLOOD platelet aggregation , *ANGIOTENSIN I - Abstract
The Alzheimer's disease leads to neurodegenerative processes and affecting negatively million people worldwide. The treatment of the disease is still difficult and incomplete in practice. Galanthamine is one of the most commonly used drugs against the illness. The main aim of this work is design and synthesis of new derivatives of galanthamine comprising peptide moiety as well as study of their β-secretase inhibitory activity and the anti-aggregating effect. All new derivatives of galanthamine containing analogues of Leu-Val-Phe-Phe (Aβ17-Aβ20) were synthesized in solution using fragment and consecutive condensation approaches. The new derivatives were characterized by melting points, NMR, and HPLC/MS. They were tested in vitro for β-secretase inhibition activity by means of fluorescent method and were investigated in vitro for anti-aggregation activity on sheep platelet-rich plasma. Although the new compounds do not contain a structural element responsible for the β-secretase inhibition, five of them show high or good β-secretase inhibitory activity between 19.98 and 51.19% with IC50 between 1.95 and 5.26 nM. Four of the new molecules were able to inhibit platelet aggregation between 55.0 and 90.0% with IC50 between 0.69 and 1.36 µM. Four of the compounds were able to inhibit platelet aggregation and two of them have high anti-aggregating effects. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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10. MT5-MMP promotes neuroinflammation, neuronal excitability and Aβ production in primary neuron/astrocyte cultures from the 5xFAD mouse model of Alzheimer's disease.
- Author
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Pilat, Dominika, Paumier, Jean-Michel, García-González, Laura, Louis, Laurence, Stephan, Delphine, Manrique, Christine, Khrestchatisky, Michel, Di Pasquale, Eric, Baranger, Kévin, and Rivera, Santiago
- Subjects
- *
ASTROCYTES , *ALZHEIMER'S disease , *AMYLOID beta-protein , *NEUROINFLAMMATION , *LABORATORY mice , *PERIPHERAL nervous system - Abstract
Background: Membrane-type matrix metalloproteinase 5 (MT5-MMP) deficiency in the 5xFAD mouse model of Alzheimer's disease (AD) reduces brain neuroinflammation and amyloidosis, and prevents deficits in synaptic activity and cognition in prodromal stages of the disease. In addition, MT5-MMP deficiency prevents interleukin-1 beta (IL-1β)-mediated inflammation in the peripheral nervous system. In this context, we hypothesized that the MT5-MMP/IL-1β tandem could regulate nascent AD pathogenic events in developing neural cells shortly after the onset of transgene activation.Methods: To test this hypothesis, we used 11-14 day in vitro primary cortical cultures from wild type, MT5-MMP-/-, 5xFAD and 5xFAD/MT5-MMP-/- mice, and evaluated the impact of MT5-MMP deficiency and IL-1β treatment for 24 h, by performing whole cell patch-clamp recordings, RT-qPCR, western blot, gel zymography, ELISA, immunocytochemistry and adeno-associated virus (AAV)-mediated transduction.Results: 5xFAD cells showed higher levels of MT5-MMP than wild type, concomitant with higher basal levels of inflammatory mediators. Moreover, MT5-MMP-deficient cultures had strong decrease of the inflammatory response to IL-1β, as well as decreased stability of recombinant IL-1β. The levels of amyloid beta peptide (Aβ) were similar in 5xFAD and wild-type cultures, and IL-1β treatment did not affect Aβ levels. Instead, the absence of MT5-MMP significantly reduced Aβ by more than 40% while sparing APP metabolism, suggesting altogether no functional crosstalk between IL-1β and APP/Aβ, as well as independent control of their levels by MT5-MMP. The lack of MT5-MMP strongly downregulated the AAV-induced neuronal accumulation of the C-terminal APP fragment, C99, and subsequently that of Aβ. Finally, MT5-MMP deficiency prevented basal hyperexcitability observed in 5xFAD neurons, but not hyperexcitability induced by IL-1β treatment.Conclusions: Neuroinflammation and hyperexcitability precede Aβ accumulation in developing neural cells with nascent expression of AD transgenes. MT5-MMP deletion is able to tune down basal neuronal inflammation and hyperexcitability, as well as APP/Aβ metabolism. In addition, MT5-MMP deficiency prevents IL-1β-mediated effects in brain cells, except hyperexcitability. Overall, this work reinforces the idea that MT5-MMP is at the crossroads of pathogenic AD pathways that are already incipiently activated in developing neural cells, and that targeting MT5-MMP opens interesting therapeutic prospects. [ABSTRACT FROM AUTHOR]- Published
- 2022
- Full Text
- View/download PDF
11. Core/shell structural ultra-small gold and amyloid peptide nanocomposites with effective bacterial surface adherence and enhanced antibacterial photothermal ablation
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Hanmeng Gui, Yonghai Feng, Li Qiang, Tongtong Sun, and Lei Liu
- Subjects
Amyloid peptide ,Photothermal therapy ,Ultra-small Au nanoparticles ,Core/shell structure ,Bacterial affinity ,Technology - Abstract
The exploration of ultra-small gold nanoparticles (Au NPs) (
- Published
- 2021
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12. γ-Secretase modulators exhibit selectivity for modulation of APP cleavage but inverse γ-secretase modulators do not
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Christian B. Lessard, Edgardo Rodriguez, Thomas B. Ladd, Lisa M. Minter, Barbara A. Osborne, Lucio Miele, Todd E. Golde, and Yong Ran
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Presenilin ,Gene knockout ,γ-Secretase modulators (GSMs) ,Amyloid peptide ,Amyloid protein precursor (APP) ,NOTCH ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background γ-Secretase is a multiprotein protease that cleaves amyloid protein precursor (APP) and other type I transmembrane proteins. It has two catalytic subunits, presenilins 1 and 2 (PS1 and 2). In our previous report, we observed subtle differences in PS1- and PS2-mediated cleavages of select substrates and slightly different potencies of PS1 versus PS2 inhibition for select γ-secretase inhibitors (GSIs) on various substrates. In this study, we investigated whether γ-secretase modulators (GSMs) and inverse γ-secretase modulators (iGSMs) modulate γ-secretase processivity using multiple different substrates. We next used HEK 293T cell lines in which PSEN1 or PSEN2 was selectively knocked out to investigate processivity and response to GSMs and iGSMs. Methods For cell-free γ-secretase cleavage assay, recombinant substrates were incubated with CHAPSO-solubilized CHO or HEK 293T cell membrane with GSMs or iGSMs in suitable buffer. For cell-based assay, cDNA encoding substrates were transfected into HEK 293T cells. Cells were then treated with GSMs or iGSMs, and conditioned media were collected. Aβ and Aβ-like peptide production from cell-free and cell-based assay were measured by ELISA and mass spectrometry. Result These studies demonstrated that GSMs are highly selective for effects on APP, whereas iGSMs have a more promiscuous effect on many substrates. Surprisingly, iGSMs actually appear to act as like GSIs on select substrates. The data with PSEN1 or PSEN2 knocked out HEK 293T reveal that PS1 has higher processivity and response to GSMs than PS2, but PS2 has higher response to iGSM. Conclusion Collectively, these data indicate that GSMs are likely to have limited target-based toxicity. In addition, they show that iGSMs may act as substrate-selective GSIs providing a potential new route to identify leads for substrate-selective inhibitors of certain γ-secretase-mediated signaling events. With growing concerns that long-term β-secretase inhibitor is limited by target-based toxicities, such data supports continued development of GSMs as AD prophylactics.
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- 2020
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13. Alzheimer's Disease Pathophysiology and its Implications
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Choudhury, Shatabdi and Vellapandian, Chitra
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- 2019
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14. Macrochirality of Self-Assembled and Co-assembled Supramolecular Structures of a Pair of Enantiomeric Peptides
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Zhen Guo, Yongshun Song, Yujiao Wang, Tingyuan Tan, Yuwen Ji, Guangxu Zhang, Jun Hu, and Yi Zhang
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amyloid peptide ,chirality ,self-assembly ,co-assembly ,macrochirality ,Biology (General) ,QH301-705.5 - Abstract
Although macrochirality of peptides’ supramolecular structures has been found to play important roles in biological activities, how macrochirality is determined by the molecular chirality of the constituted amino acids is still unclear. Here, two chiral peptides, Ac-LKLHLHLQLKLLLVLFLFLALK-NH2 (KK-11) and Ac-DKDHDHDQDKDL DVDFDFDADK-NH2 (KKd-11), which were composed entirely of either L- or D-amino acids, were designed for studying the chiral characteristics of the supramolecular microstructures. It was found that monocomponent KK-11 or KKd-11 self-assembled into right- or left-handed helical nanofibrils, respectively. However, when they co-assembled with concentration ratios varied from 1:9 to 9:1, achiral nanowire-like structures were formed. Both circular dichroism and Fourier transform infrared spectra indicated that the secondary structures changed when the peptides co-assembled. MD simulations indicated that KK-11 or KKd-11 exhibited a strong propensity to self-assemble into right-handed or left-handed nanofibrils, respectively. However, when KK-11 and KKd-11 were both presented in a solution, they had a higher probability to co-assemble instead of self-sort. MD simulations indicated that, in their mixtures, they formed nanowires without handedness feature, a good agreement with experimental observation. Our results shed light on the molecular mechanisms of the macrochirality of peptide supramolecular microstructures.
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- 2021
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15. Mechanism Ethnomedicinal and Phytochemical Effect of Ayurvedic Plants in Prevention and Management of Senile Dementia of Alzheimer's Disease: A Review.
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KUMARI, RINKI, VERMA, ANJALI, SHARMA, DISHA, MISHRA, SUDHANSHU, SAHI, AJAY KUMAR, GUNDU, SHRAVANYA, SINGH, NANKI, SINGH, JASMEET, AZURE, SIMON AGONGO, and VENAIK, ANITA
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TRADITIONAL medicine , *PHYTOCHEMICALS , *AYURVEDIC medicine , *SENILE dementia , *ALZHEIMER'S disease prevention , *MEMORY loss - Abstract
In the current scenario, there are negligible or no approved anti-neurodegenerative therapies globally; only the conventional drugs provide very short-term relief. For centuries, due to multi-component and multi-target approaches of herbal or natural medicines have been used to treat various neurodegenerative like senile dementia and Alzheimer's disease. The present review reveals several most prominent medicinal plants and their respective constituents, utilized in traditional medicine systems for cognitive impairment treatment, and various biomarkers have been discussed. This review attempts to direct the urgent need for new and proved herbal therapeutic agents to obviate neurogenesis. Most of predominant neuro-degenerative such as Alzheimer's disease has ailment characterized by progressive cognitive deterioration. This highlights the urgent need for new and improved herbal-based therapeutic agents to obviate neurogenesis. Various biomarkers have been well established which diagnose neurodegenerative diseases such as SD (Full Form) and AD, which is linked with an assortment of symptoms, nowadays almost 100 impending new herbal medicines are currently developed. The present review is expected to provide an into the current progress of herbal antineurodegenerative drugs, with a particular focus on their mechanism to escort target. We expect this review to provide a rational perspective-management vision on the significance of future anti-neurodegenerative herbal preparations to be effective in the preclusion and managing various neurodegenerative. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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16. Concentration‐Dependent Interactions of Amphiphilic PiB Derivative Metal Complexes with Amyloid Peptides Aβ and Amylin**.
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Majdoub, Saida, Garda, Zoltán, Oliveira, Alexandre C., Relich, Inga, Pallier, Agnès, Lacerda, Sara, Hureau, Christelle, Geraldes, Carlos F. G. C., Morfin, Jean‐François, and Tóth, Éva
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METAL complexes , *PEPTIDES , *SURFACE plasmon resonance , *AMYLOID , *AMYLIN , *ALZHEIMER'S disease - Abstract
Metal chelates targeted to amyloid peptides are widely explored as diagnostic tools or therapeutic agents. The attachment of a metal complex to amyloid recognition units typically leads to a decrease in peptide affinity. We show here that by separating a macrocyclic GdL chelate and a PiB targeting unit with a long hydrophobic C10 linker, it is possible to attain nanomolar affinities for both Aβ1‐40 (Kd=4.4 nm) and amylin (Kd=4.5 nm), implicated, respectively in Alzheimer's disease and diabetes. The Scatchard analysis of surface plasmon resonance data obtained for a series of amphiphilic, PiB derivative GdL complexes indicate that their Aβ1‐40 or amylin binding affinity varies with their concentration, thus micellar aggregation state. The GdL chelates also affect peptide aggregation kinetics, as probed by thioflavin‐T fluorescence assays. A 2D NMR study allowed identifying that the hydrophilic region of Aβ1‐40 is involved in the interaction between the monomer peptide and the Gd3+ complex. Finally, ex vivo biodistribution experiments were conducted in healthy mice by using 111In labeled analogues. Their pancreatic uptake, ∼3 %ID g−1, is promising to envisage amylin imaging in diabetic animals. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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17. CD36 in Alzheimer's Disease: An Overview of Molecular Mechanisms and Therapeutic Targeting.
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Dobri, Ana-Maria, Dudău, Maria, Enciu, Ana-Maria, and Hinescu, Mihail Eugen
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ALZHEIMER'S disease , *LOW density lipoproteins , *SMALL molecules , *MEMBRANE proteins , *FRACTALKINE , *MONOCLONAL antibodies , *NEUROBIOLOGY - Abstract
• CD 36 is a microglial scavenger receptor, involved in Aβ clearance. • In AD brain, pro-inflammatory microglia downregulates CD36 expression. • Pharmacologic manipulation of CD36 improved Aβ clearance in AD mouse models. • There are insufficient clinical data of CD36 involvement in AD. CD36 is a membrane protein with wide distribution in the human body, is enriched in the monocyte-macrophage system and endothelial cells, and is involved in the cellular uptake of long chain fatty acids (LCFA) and oxidized low-density lipoproteins. It is also a scavenger receptor, binding hydrophobic amyloid fibrils found in the Alzheimer's disease (AD) brain. In neurobiology research, it has been mostly studied in relationship with chronic ischemia and stroke, but it was also related to amyloid clearance by microglial phagocytosis. In AD animal models, amyloid binding to CD36 has been consistently correlated with a pro-inflammatory response. Therapeutic approaches have two main focuses: CD36 blockade with monoclonal antibodies or small molecules, which is beneficial in terms of the inflammatory milieu, and upregulation of CD36 for increased amyloid clearance. The balance of the two approaches, centered on microglia, is poorly understood. Furthermore, CD36 evaluation in AD clinical studies is still at a very early stage and there is a gap in the knowledge regarding the impact of LCFA on AD progression and CD36 expression and genetic phenotype. This review summarizes the role played by CD36 in the pathogenic amyloid cascade and explore the translatability of preclinical data towards clinical research. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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18. Incremental Value of CSF Biomarkers in Clinically Diagnosed AD and Non-AD Dementia
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Jean-Baptiste Oudart, Zoubir Djerada, Vignon Nonnonhou, Sarah Badr, Laurie-Anne Bertholon, Anis Dammak, Yacine Jaidi, Jean-Luc Novella, Nicolas Pallet, Philippe Gillery, and Rachid Mahmoudi
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Alzheimer disease ,CSF biomarkers ,amyloid peptide ,cut-off values ,diagnostic algorithm ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Background: Cerebrospinal fluid (CSF) biomarkers are used to diagnose Alzheimer disease (AD), especially in atypical clinical presentations. No consensus currently exists regarding cut-off values. This study aimed, firstly, to define optimal cut-off values for CSF biomarkers, and secondly, to investigate the most relevant diagnostic strategy for AD based on CSF biomarker combinations.Methods: A total of 380 patients were prospectively included: 140 with AD, 240 with various neurological diagnoses (non-AD). CSF biomarkers were measured using ELISA. Univariate and multivariate analyses were performed using random forest and logistic regression approaches.Results: Univariate receiver operating curve curves analysis of T-Tau, P-Tau181, Aβ42, Aβ40 concentrations, and Aβ42/Aβ40 ratio levels showed AD cut-off values of ≥355, ≥57, ≤706, ≥10,854, and ≤0.059 ng/L, respectively. Multivariate analysis using random forest and logistic regression found that the algorithm based on P-Tau181, Aβ42 concentrations and Aβ42/Aβ40 ratio yielded the best discrimination between AD and non-AD populations. The cross-validation technique of the final model showed a mean accuracy of 0.85 and a mean AUC of 0.89.Conclusion: This study confirms that the Aβ42/Aβ40 ratio was more useful than the Aβ40 concentration in discriminating AD from non-AD populations in daily practice. These results indicate that the Aβ42/Aβ40 ratio should be assessed in all cases, independently of Aβ42 concentrations.
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- 2020
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19. Molecular dynamics simulations of copper binding to amyloid-β Glu22 mutants
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Shaun T. Mutter, Matthew Turner, Robert J. Deeth, and James A. Platts
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Theoretical chemistry ,Molecular dynamics ,Copper ,Salt bridges ,Amyloid peptide ,Science (General) ,Q1-390 ,Social sciences (General) ,H1-99 - Abstract
We report microsecond timescale ligand field molecular dynamics simulations of the copper complexes of three known mutants of the amyloid-β peptide, E22G, E22Q and E22K, alongside the naturally occurring sequence. We find that all three mutants lead to formation of less compact structures than the wild-type: E22Q is the most similar to the native peptide, while E22G and especially E22K are markedly different in size, shape and stability. Turn and coil structures dominate all structures studied but subtle differences in helical and β-sheet distribution are noted, especially in the C-terminal region. The origin of these changes is traced to disruption of key salt bridges: in particular, the Asp23-Lys28 bridge that is prevalent in the wild-type is absent in E22G and E22K, while Lys22 in the latter mutant forms a strong association with Asp23. We surmise that the drastically different pattern of salt bridges in the mutants lead to adoption of a different structural ensemble of the peptide backbone, and speculate that this might affect the ability of the mutant peptides to aggregate in the same manner as known for the wild-type.
- Published
- 2020
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20. Natural polyphenols effects on protein aggregates in Alzheimer's and Parkinson's prion-like diseases
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Aline Freyssin, Guylène Page, Bernard Fauconneau, and Agnès Rioux Bilan
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natural polyphenols ,protein aggregates ,Alzheimer′s disease ,amyloid peptide ,amyloid plaques ,hyperphosphorylated tau ,Parkinson′s disease ,α-synuclein ,synphilin-1 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Alzheimer's and Parkinson's diseases are the most common neurodegenerative diseases. They are characterized by protein aggregates and so can be considered as prion-like disease. The major components of these deposits are amyloid peptide and tau for Alzheimer's disease, α-synuclein and synphilin-1 for Parkinson's disease. Drugs currently proposed to treat these pathologies do not prevent neurodegenerative processes and are mainly symptomatic therapies. Molecules inducing inhibition of aggregation or disaggregation of these proteins could have beneficial effects, especially if they have other beneficial effects for these diseases. Thus, several natural polyphenols, which have antioxidative, anti-inflammatory and neuroprotective properties, have been largely studied, for their effects on protein aggregates found in these diseases, notably in vitro. In this article, we propose to review the significant papers concerning the role of polyphenols on aggregation and disaggregation of amyloid peptide, tau, α-synuclein, synphilin-1, suggesting that these compounds could be useful in the treatments in Alzheimer's and Parkinson's diseases.
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- 2018
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21. Incremental Value of CSF Biomarkers in Clinically Diagnosed AD and Non-AD Dementia.
- Author
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Oudart, Jean-Baptiste, Djerada, Zoubir, Nonnonhou, Vignon, Badr, Sarah, Bertholon, Laurie-Anne, Dammak, Anis, Jaidi, Yacine, Novella, Jean-Luc, Pallet, Nicolas, Gillery, Philippe, and Mahmoudi, Rachid
- Subjects
BIOMARKERS ,DEMENTIA ,CEREBROSPINAL fluid ,MULTIVARIATE analysis ,UNIVARIATE analysis - Abstract
Background: Cerebrospinal fluid (CSF) biomarkers are used to diagnose Alzheimer disease (AD), especially in atypical clinical presentations. No consensus currently exists regarding cut-off values. This study aimed, firstly, to define optimal cut-off values for CSF biomarkers, and secondly, to investigate the most relevant diagnostic strategy for AD based on CSF biomarker combinations. Methods: A total of 380 patients were prospectively included: 140 with AD, 240 with various neurological diagnoses (non-AD). CSF biomarkers were measured using ELISA. Univariate and multivariate analyses were performed using random forest and logistic regression approaches. Results: Univariate receiver operating curve curves analysis of T-Tau, P-Tau
181 , Aβ42 , Aβ40 concentrations, and Aβ42 /Aβ40 ratio levels showed AD cut-off values of ≥355, ≥57, ≤706, ≥10,854, and ≤0.059 ng/L, respectively. Multivariate analysis using random forest and logistic regression found that the algorithm based on P-Tau181 , Aβ42 concentrations and Aβ42 /Aβ40 ratio yielded the best discrimination between AD and non-AD populations. The cross-validation technique of the final model showed a mean accuracy of 0.85 and a mean AUC of 0.89. Conclusion: This study confirms that the Aβ42 /Aβ40 ratio was more useful than the Aβ40 concentration in discriminating AD from non-AD populations in daily practice. These results indicate that the Aβ42 /Aβ40 ratio should be assessed in all cases, independently of Aβ42 concentrations. [ABSTRACT FROM AUTHOR]- Published
- 2020
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22. γ-Secretase modulators exhibit selectivity for modulation of APP cleavage but inverse γ-secretase modulators do not.
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Lessard, Christian B., Rodriguez, Edgardo, Ladd, Thomas B., Minter, Lisa M., Osborne, Barbara A., Miele, Lucio, Golde, Todd E., and Ran, Yong
- Subjects
- *
AMYLOID beta-protein precursor , *MEMBRANE proteins , *MASS spectrometry , *CELL membranes - Abstract
Background: γ-Secretase is a multiprotein protease that cleaves amyloid protein precursor (APP) and other type I transmembrane proteins. It has two catalytic subunits, presenilins 1 and 2 (PS1 and 2). In our previous report, we observed subtle differences in PS1- and PS2-mediated cleavages of select substrates and slightly different potencies of PS1 versus PS2 inhibition for select γ-secretase inhibitors (GSIs) on various substrates. In this study, we investigated whether γ-secretase modulators (GSMs) and inverse γ-secretase modulators (iGSMs) modulate γ-secretase processivity using multiple different substrates. We next used HEK 293T cell lines in which PSEN1 or PSEN2 was selectively knocked out to investigate processivity and response to GSMs and iGSMs. Methods: For cell-free γ-secretase cleavage assay, recombinant substrates were incubated with CHAPSO-solubilized CHO or HEK 293T cell membrane with GSMs or iGSMs in suitable buffer. For cell-based assay, cDNA encoding substrates were transfected into HEK 293T cells. Cells were then treated with GSMs or iGSMs, and conditioned media were collected. Aβ and Aβ-like peptide production from cell-free and cell-based assay were measured by ELISA and mass spectrometry. Result: These studies demonstrated that GSMs are highly selective for effects on APP, whereas iGSMs have a more promiscuous effect on many substrates. Surprisingly, iGSMs actually appear to act as like GSIs on select substrates. The data with PSEN1 or PSEN2 knocked out HEK 293T reveal that PS1 has higher processivity and response to GSMs than PS2, but PS2 has higher response to iGSM. Conclusion: Collectively, these data indicate that GSMs are likely to have limited target-based toxicity. In addition, they show that iGSMs may act as substrate-selective GSIs providing a potential new route to identify leads for substrate-selective inhibitors of certain γ-secretase-mediated signaling events. With growing concerns that long-term β-secretase inhibitor is limited by target-based toxicities, such data supports continued development of GSMs as AD prophylactics. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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23. A Study on the Effect of Seven Different Compounds of Cannabis Extract on the Accumulation of Amyloid Peptide in Alzheimer\'s Disease through Molecular Simulations
- Author
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Faezeh Jalalian and Ali Jebali
- Subjects
amyloid peptide ,alzheimer's disease ,cannabis extract ,simulation ,molecular dynamics ,Computer applications to medicine. Medical informatics ,R858-859.7 ,Medical technology ,R855-855.5 - Abstract
Introduction: Alzheimer's disease is a progressive cerebrovascular disease with irreversible damage, which gradually degrades the mental abilities of the patient. In this study, amyloid peptide was exposed to seven different compounds in the canaboid extract and then, the structure and thermodynamic parameters were evaluated. Methods: In this study, the three-dimensional structure of beta-amyloid peptide in patients with Alzheimer's disease was prepared from the rcsb database. The main components of canaboid extract were obtained from CHEBI database too. Then, amyloid peptide was subjected to each of the canaboid extract molecules in the molecular dynamics simulation software, and its structural and thermodynamic characteristics were evaluated over 3000 picoseconds. Results: Comparison of seven different compounds of cannabis extract showed that all cannabis extract compounds were able to change the structure of amyloid peptide. Each compound was able to change the effective surface and volume, and the level of lipophilicty of amyloid peptides. Conclusion: The ability of these compounds to change the volume and surface is effective in preventing amyloid peptide accumulation. The findings of this study should be investigated in a laboratory scale and then on the human body to detect the efficacy of canaboid extract components exactly.
- Published
- 2017
24. Conclusion and Future Perspectives
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Tinker-Mill, Claire Louisa and Tinker-Mill, Claire Louisa
- Published
- 2016
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25. Exploring the Early Stages of the Amyloid Aβ(1–42) Peptide Aggregation Process: An NMR Study
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Angelo Santoro, Manuela Grimaldi, Michela Buonocore, Ilaria Stillitano, and Anna Maria D’Ursi
- Subjects
Alzheimer’s disease ,amyloid peptide ,NMR structure ,Aβ(1–42) ,molecular dynamics ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
Alzheimer’s disease (AD) is a neurodegenerative pathology characterized by the presence of neurofibrillary tangles and amyloid plaques, the latter mainly composed of Aβ(1–40) and Aβ(1–42) peptides. The control of the Aβ aggregation process as a therapeutic strategy for AD has prompted the interest to investigate the conformation of the Aβ peptides, taking advantage of computational and experimental techniques. Mixtures composed of systematically different proportions of HFIP and water have been used to monitor, by NMR, the conformational transition of the Aβ(1–42) from soluble α-helical structure to β-sheet aggregates. In the previous studies, 50/50 HFIP/water proportion emerged as the solution condition where the first evident Aβ(1–42) conformational changes occur. In the hypothesis that this solvent reproduces the best condition to catch transitional helical-β-sheet Aβ(1–42) conformations, in this study, we report an extensive NMR conformational analysis of Aβ(1–42) in 50/50 HFIP/water v/v. Aβ(1–42) structure was solved by us, giving evidence that the evolution of Aβ(1–42) peptide from helical to the β-sheet may follow unexpected routes. Molecular dynamics simulations confirm that the structural model we calculated represents a starting condition for amyloid fibrils formation.
- Published
- 2021
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26. Molecular Modulation of Human α7 Nicotinic Receptor by Amyloid-β Peptides
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Matías Lasala, Camila Fabiani, Jeremías Corradi, Silvia Antollini, and Cecilia Bouzat
- Subjects
nicotinic receptor ,patch-clamp recordings ,single-channel currents ,Cys-loop receptor ,amyloid peptide ,crystal violet ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Amyloid β peptide (Aβ) is a key player in the development of Alzheimer’s disease (AD). It is the primary component of senile plaques in AD patients and is also found in soluble forms. Cholinergic activity mediated by α7 nicotinic receptors has been shown to be affected by Aβ soluble forms. To shed light into the molecular mechanism of this effect, we explored the direct actions of oligomeric Aβ1–40 and Aβ1–42 on human α7 by fluorescence spectroscopy and single-channel recordings. Fluorescence measurements using the conformational sensitive probe crystal violet (CrV) revealed that in the presence of Aβ α7 undergoes concentration-dependent conformational changes. Exposure of α7 to 100 pM Aβ changes CrV KD towards that of the desensitized state. However, α7 is still reactive to high carbamylcholine (Carb) concentrations. These observations are compatible with the induction of active/desensitized states as well as of a novel conformational state in the presence of both Aβ and Carb. At 100 nM Aβ, α7 adopts a resting-state-like structure which does not respond to Carb, suggesting stabilization of α7 in a blocked state. In real time, we found that Aβ is capable of eliciting α7 channel activity either in the absence or presence of the positive allosteric modulator (PAM) PNU-120596. Activation by Aβ is favored at picomolar or low nanomolar concentrations and is not detected at micromolar concentrations. At high Aβ concentrations, the mean duration of activation episodes elicited by ACh in the presence of PNU-120596 is significantly reduced, an effect compatible with slow open-channel block. We conclude that Aβ directly affects α7 function by acting as an agonist and a negative modulator. Whereas the capability of low concentrations of Aβ to activate α7 could be beneficial, the reduced α7 activity in the presence of higher Aβ concentrations or its long exposure may contribute to the cholinergic signaling deficit and may be involved in the initiation and development of AD.
- Published
- 2019
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27. Effect of Proinflammatory S100A9 Protein on Migration and Proliferation of Microglial Cells.
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Bai Q, Sun D, Zeng Y, Zhu J, Zhang C, Zhang X, Chen L, Zhou X, Ye L, Tang Y, Liu Y, and Morozova-Roche LA
- Subjects
- Amyloid beta-Peptides toxicity, Amyloid beta-Peptides metabolism, Interleukin-6 metabolism, Microglia metabolism, Plaque, Amyloid metabolism, Tumor Necrosis Factor-alpha metabolism, Animals, Mice, Alzheimer Disease metabolism, Calgranulin B genetics, Calgranulin B metabolism, Calgranulin B pharmacology
- Abstract
Alzheimer's disease (AD) is a multifactorial disease affecting aging population worldwide. Neuroinflammation became a focus of research as one of the major pathologic processes relating to the disease onset and progression. Proinflammatory S100A9 is the central culprit in the amyloid-neuroinflammatory cascade implicated in AD and other neurodegenerative diseases. We studied the effect of S100A9 on microglial BV-2 cell proliferation and migration. The responses of BV-2 cells to S100A9 stimulation were monitored in real-time using live cell microscopy, transcriptome sequencing, immunofluorescence staining, western blot analysis, and ELISA. We observed that a low dose of S100A9 promotes migration and proliferation of BV-2 cells. However, acute inflammatory condition (i.e., high S100A9 doses) causes diminished cell viability; it is uncovered that S100A9 activates TLR-4 and TLR-7 signaling pathways, leading to TNF-α and IL-6 expression, which affect BV-2 cell migration and proliferation in a concentration-dependent manner. Interestingly, the effects of S100A9 are not only inhibited by TNF-α and IL-6 antibodies. The addition of amyloid-β (Aβ) 1-40 peptide resumes the capacities of BV-2 cells to the level of low S100A9 concentrations. Based on these results, we conclude that in contrast to the beneficial effects of low S100A9 dose, high S100A9 concentration leads to impaired mobility and proliferation of immune cells, reflecting neurotoxicity at acute inflammatory conditions. However, the formation of Aβ plaques may be a natural mechanism that rescues cells from the proinflammatory and cytotoxic effects of S100A9, especially considering that inflammation is one of the primary causes of AD., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2023
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28. The Neurovascular Unit Dysfunction in Alzheimer’s Disease
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Luis O. Soto-Rojas, Mar Pacheco-Herrero, Paola A. Martínez-Gómez, B. Berenice Campa-Córdoba, Ricardo Apátiga-Pérez, Marcos M. Villegas-Rojas, Charles R. Harrington, Fidel de la Cruz, Linda Garcés-Ramírez, and José Luna-Muñoz
- Subjects
blood-brain barrier ,astrocytes ,microglia ,amyloid peptide ,Alzheimer’s disease ,tau protein ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide. Histopathologically, AD presents with two hallmarks: neurofibrillary tangles (NFTs), and aggregates of amyloid β peptide (Aβ) both in the brain parenchyma as neuritic plaques, and around blood vessels as cerebral amyloid angiopathy (CAA). According to the vascular hypothesis of AD, vascular risk factors can result in dysregulation of the neurovascular unit (NVU) and hypoxia. Hypoxia may reduce Aβ clearance from the brain and increase its production, leading to both parenchymal and vascular accumulation of Aβ. An increase in Aβ amplifies neuronal dysfunction, NFT formation, and accelerates neurodegeneration, resulting in dementia. In recent decades, therapeutic approaches have attempted to decrease the levels of abnormal Aβ or tau levels in the AD brain. However, several of these approaches have either been associated with an inappropriate immune response triggering inflammation, or have failed to improve cognition. Here, we review the pathogenesis and potential therapeutic targets associated with dysfunction of the NVU in AD.
- Published
- 2021
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29. Rho-associated kinases contribute to the regulation of tau phosphorylation and amyloid metabolism during neuronal plasticity
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Saray, Hatice, Süer, Cem, Koşar, Bilal, Tan, Burak, and Dursun, Nurcan
- Published
- 2021
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30. Analytical and clinical performances of the automated Lumipulse cerebrospinal fluid Aβ42 and T-Tau assays for Alzheimer's disease diagnosis.
- Author
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Bayart, Jean-Louis, Hanseeuw, Bernard, Ivanoiu, Adrian, and van Pesch, Vincent
- Subjects
- *
ALZHEIMER'S disease , *CEREBROSPINAL fluid - Abstract
Background: Cerebrospinal fluid (CSF) biomarkers are increasingly used to diagnose Alzheimer's disease (AD). However, important methodological and technical remain regarding measurement variability between kit providers and users. We compared the Lumipulse fully automated assays with the manual INNOTEST assays (both from Fujirebio Europe NV, Gent, Belgium) on a clinically representative sample of patients and controls. Methods: CSF samples of 156 patients were used to quantify Amyloïd Aβ1–42 peptide (Aβ1–42) and Total-Tau (T-Tau) protein by chemiluminescent enzyme-immunoassay (Lumipulse). Patients were divided into several subgroups: Alzheimer (AD = 44), mild-cognitive impairment (MCI = 23), other dementias (OD = 36), non-dementing neurological conditions (ND = 11), and controls (CTRL = 42). Clinical cut-offs were determined by comparing AD and CTRL with ROC curves for the two markers and their related ratio (T-Tau/Aβ1–42). Subgroups of 58 (for phosphorylated-Tau) and 115 samples (for Aβ1–42 and T-Tau) were used to evaluate the concordance of this analyzer with the INNOTEST assays. Results: Lumipulse and INNOTEST assays showed good concordance for all markers, but systematic bias was observed justifying the need to redefine new clinical cut-offs. To discriminate AD from CTRL subjects, T-Tau/Aβ1–42 ratio was the best biomarker, with a cut-off value of 1.12 (sensitivity 81.8% and specificity 92.9%). Similar clinical performances were observed for the Lumipulse and Innotests assays on the subsample of 115 subjects. Conclusions: Our results demonstrate that the Lumipulse Aβ1–42 and T-Tau assays show good analytical and clinical performances in the context of patient evaluation referred to a memory clinic. Automated analyzers should be preferred for the measurement of CSF AD biomarkers to reduce inter- and intra-laboratory variability. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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31. Multidisciplinary approaches for targeting the secretase protein family as a therapeutic route for Alzheimer's disease.
- Author
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Schaduangrat, Nalini, Prachayasittikul, Veda, Choomwattana, Saowapak, Wongchitrat, Prapimpun, Phopin, Kamonrat, Suwanjang, Wilasinee, Malik, Aijaz Ahmad, Vincent, Bruno, and Nantasenamat, Chanin
- Subjects
ALZHEIMER'S disease - Abstract
The continual increase of the aging population worldwide renders Alzheimer's disease (AD) a global prime concern. Several attempts have been focused on understanding the intricate complexity of the disease's development along with the on‐ andgoing search for novel therapeutic strategies. Incapability of existing AD drugs to effectively modulate the pathogenesis or to delay the progression of the disease leads to a shift in the paradigm of AD drug discovery. Efforts aimed at identifying AD drugs have mostly focused on the development of disease‐modifying agents in which effects are believed to be long lasting. Of particular note, the secretase enzymes, a group of proteases responsible for the metabolism of the β‐amyloid precursor protein (βAPP) and β‐amyloid (Aβ) peptides production, have been underlined for their promising therapeutic potential. This review article attempts to comprehensively cover aspects related to the identification and use of drugs targeting the secretase enzymes. Particularly, the roles of secretases in the pathogenesis of AD and their therapeutic modulation are provided herein. Moreover, an overview of the drug development process and the contribution of computational (in silico) approaches for facilitating successful drug discovery are also highlighted along with examples of relevant computational works. Promising chemical scaffolds, inhibitors, and modulators against each class of secretases are also summarized herein. Additionally, multitarget secretase modulators are also taken into consideration in light of the current growing interest in the polypharmacology of complex diseases. Finally, challenging issues and future outlook relevant to the discovery of drugs targeting secretases are also discussed. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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32. Herpesviral infections and antimicrobial protection for Alzheimer's disease: Implications for prevention and treatment.
- Author
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Qin, Qingsong and Li, Yun
- Subjects
TAU proteins ,ALZHEIMER'S disease ,THERAPEUTICS ,PREVENTIVE medicine ,AMYLOID plaque ,NEUROFIBRILLARY tangles ,AMYLOID beta-protein ,HERPESVIRUS diseases - Abstract
Accumulating evidence suggests that infections by herpesviruses might be closely linked to Alzheimer's disease (AD). Pathological hallmarks of AD brains include senile plaques induced by amyloid β peptide (Aβ) in the extracellular space and intracellular neurofibrillary tangles (NFTs) consisting of phosphorylated tau protein. The prevailing hypothesis for the mechanism of AD is amyloid cascade reaction. Recent studies revealed that infections by herpesviruses induce the similar pathological hallmarks of AD, including Aβ production, phosphorylation of tau (P‐tau), oxidative stress, neuroinflammation, etc. Aβ peptide is regarded as one of the antimicrobial peptides, which inhibits HSV‐1 replication. In the elderly, reactivation of herpesviruses might act as an initiator for amyloid cascade reaction in vulnerable individuals, triggering the neurofibrillary formation of phosphorylated tau and inducing oxidative stress and neuroinflammation, which can further contribute to the accumulation of Aβ and P‐tau by impairing mitochondria and autophagosome. Epidemiological studies have shown AD susceptibility genes, such as APOE‐ε4 allele, are highly linked to infections by herpesviruses. Interestingly, anti‐herpesviral therapy significantly reduced the risk of AD in a large population study. Given that herpesviruses are arguably the most prevalent opportunistic pathogens and often reactivate in the elderly, it is reasonable to argue reactivation of herpesviruses might be major culprits for initiating AD in individuals carrying AD susceptibility genes. In this review, we summarize epidemiological and molecular evidence that support for a hypothesis of herpesviral infections and antimicrobial protection in the development of AD, and discuss the implications for future prevention and treatment of the disease. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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33. A comprehensive study on the generation of reactive oxygen species in Cu-Aβ-catalyzed redox processes.
- Author
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Huang, Hong, Lou, Xiaobing, Hu, Bingwen, Zhou, Zhongneng, Chen, Jinquan, and Tian, Yang
- Subjects
- *
ELECTRON paramagnetic resonance spectroscopy , *REACTIVE oxygen species , *ELECTRON paramagnetic resonance , *COPPER isotopes , *AMYLOID plaque , *OXIDATIVE stress - Abstract
In the amyloid plaques, a signature of AD, abnormally high Cu2+ concentrations are found bound to Aβ. Most of previous studies reported that Cu-Aβ could contribute to oxidative stress, as H 2 O 2 and •OH are catalytically generated by Cu-Aβ with the assistance of biological reductant, with only one recent report stated that free O 2 •- is also generated in the Cu-Aβ catalyzed processes, where an indirect technique was applied. To comprehensively investigate the free radicals produced during this Cu-Aβ-mediated process with a biological reductant, DNA-cleavage assay, an indirect method, and two direct methods including electron paramagnetic resonance (EPR) spectroscopy and transient absorption spectroscopy (TAS), both having qualitative and quantitative power, were employed in this work. All the experimental results obtained from the three methods demonstrated that Cu-Aβ in the biological reducing environment was not only able to catalyze the production of H 2 O 2 and •OH, but also to generate free O 2 •-. The results further indicated that O 2 •- was the precursor of H 2 O 2 and •OH. It is also important to note that the results obtained from EPR spectroscopy and TAS provided direct evidence for the presence of O 2 •- and •OH. By virtue of the direct techniques, we also found that the longest peptide fragments of Aβ 16 , Aβ 40 , and Aβ 42 produced the least radicals with a lowest rate. More interestingly, the fibrillar forms of Aβ generated less O 2 •- and •OH compared with oligomeric and monomeric forms. We have systematically investigated the Cu-Aβ-catalyzed redox cycling processes using three different methods including DNA-cleavage assay, electron paramagnetic resonance spectroscopy, and transient absorption spectroscopy. All the experimental results strongly confirm the generation of both free O 2 •- and •OH in the Cu-Aβ-catalyzed processes. Image 1 • The Cu-Aβ-catalyzed redox cycling processes had been systematically investigated using three different methods. • The results obtained by electron paramagnetic resonance spectroscopy and transient absorption spectroscopy showed direct evidence of the presence of O 2 •- and •OH. • The effects of various Aβ fragments/forms complexed with Cu2+ on the generation of O 2 •- and •OH was studied. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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34. Thyroid Hormone Supplementation Restores Spatial Memory, Hippocampal Markers of Neuroinflammation, Plasticity-Related Signaling Molecules, and β-Amyloid Peptide Load in Hypothyroid Rats.
- Author
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Chaalal, Amina, Poirier, Roseline, Blum, David, Laroche, Serge, and Enderlin, Valérie
- Abstract
Hypothyroidism is a condition that becomes more prevalent with age. Patients with untreated hypothyroidism have consistently reported symptoms of severe cognitive impairments. In patients suffering hypothyroidism, thyroid hormone supplementation offers the prospect to alleviate the cognitive consequences of hypothyroidism; however, the therapeutic value of TH supplementation remains at present uncertain and the link between cellular modifications associated with hypothyroidism and neurodegeneration remains to be elucidated. In the present study, we therefore evaluated the molecular and behavioral consequences of T3 hormone replacement in an animal model of hypothyroidism. We have previously reported that the antithyroid molecule propylthiouracil (PTU) given in the drinking water favors cerebral atrophy, brain neuroinflammation, Aβ production, Tau hyperphosphorylation, and altered plasticity-related cell-signaling pathways in the hippocampus in association with hippocampal-dependent spatial memory deficits. In the present study, our aim was to explore, in this model, the effect of hippocampal T3 signaling normalization on various molecular mechanisms involved in learning and memory that goes awry under conditions of hypothyroidism and to evaluate its potential for recovery of hippocampal-dependent memory deficits. We report that T3 supplementation can alleviate hippocampal-dependent memory impairments displayed by hypothyroid rats and normalize key markers of thyroid status in the hippocampus, of neuroinflammation, Aβ production, and of cell-signaling pathways known to be involved in synaptic plasticity and memory function. Together, these findings suggest that normalization of hippocampal T3 signaling is sufficient to reverse molecular and cognitive dysfunctions associated with hypothyroidism. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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35. Effect of a Short Peptide with Alternating L- and D-Amino Acid on the Aggregation and Membrane Damage of hIAPP
- Author
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Meng, Feihong, Wang, Yajie, Lu, Tong, Wang, Chunyu, and Li, Fei
- Published
- 2021
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36. Ginkgolides and Their Derivatives: Synthetic and Bioorganic Studies
- Author
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Dzyuba, Sergei V., Jameson, Laramie P., Nakanishi, Koji, Wagner, Hildebert, editor, and Ulrich-Merzenich, Gudrun, editor
- Published
- 2013
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37. Ensemble cryoEM elucidates the mechanism of insulin capture and degradation by human insulin degrading enzyme
- Author
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Zhening Zhang, Wenguang G Liang, Lucas J Bailey, Yong Zi Tan, Hui Wei, Andrew Wang, Mara Farcasanu, Virgil A Woods, Lauren A McCord, David Lee, Weifeng Shang, Rebecca Deprez-Poulain, Benoit Deprez, David R Liu, Akiko Koide, Shohei Koide, Anthony A Kossiakoff, Sheng Li, Bridget Carragher, Clinton S Potter, and Wei-Jen Tang
- Subjects
insulin ,amyloid peptide ,insulin degrading enzyme ,proteostasis ,cryoEM ,integrative structural biology ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Insulin degrading enzyme (IDE) plays key roles in degrading peptides vital in type two diabetes, Alzheimer's, inflammation, and other human diseases. However, the process through which IDE recognizes peptides that tend to form amyloid fibrils remained unsolved. We used cryoEM to understand both the apo- and insulin-bound dimeric IDE states, revealing that IDE displays a large opening between the homologous ~55 kDa N- and C-terminal halves to allow selective substrate capture based on size and charge complementarity. We also used cryoEM, X-ray crystallography, SAXS, and HDX-MS to elucidate the molecular basis of how amyloidogenic peptides stabilize the disordered IDE catalytic cleft, thereby inducing selective degradation by substrate-assisted catalysis. Furthermore, our insulin-bound IDE structures explain how IDE processively degrades insulin by stochastically cutting either chain without breaking disulfide bonds. Together, our studies provide a mechanism for how IDE selectively degrades amyloidogenic peptides and offers structural insights for developing IDE-based therapies.
- Published
- 2018
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38. Stabilization and structural analysis of a membrane-associated hIAPP aggregation intermediate
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Diana C Rodriguez Camargo, Kyle J Korshavn, Alexander Jussupow, Kolio Raltchev, David Goricanec, Markus Fleisch, Riddhiman Sarkar, Kai Xue, Michaela Aichler, Gabriele Mettenleiter, Axel Karl Walch, Carlo Camilloni, Franz Hagn, Bernd Reif, and Ayyalusamy Ramamoorthy
- Subjects
membrane ,Amyloid peptide ,Structure ,NMR ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Membrane-assisted amyloid formation is implicated in human diseases, and many of the aggregating species accelerate amyloid formation and induce cell death. While structures of membrane-associated intermediates would provide tremendous insights into the pathology and aid in the design of compounds to potentially treat the diseases, it has not been feasible to overcome the challenges posed by the cell membrane. Here, we use NMR experimental constraints to solve the structure of a type-2 diabetes related human islet amyloid polypeptide intermediate stabilized in nanodiscs. ROSETTA and MD simulations resulted in a unique β-strand structure distinct from the conventional amyloid β-hairpin and revealed that the nucleating NFGAIL region remains flexible and accessible within this isolated intermediate, suggesting a mechanism by which membrane-associated aggregation may be propagated. The ability of nanodiscs to trap amyloid intermediates as demonstrated could become one of the most powerful approaches to dissect the complicated misfolding pathways of protein aggregation.
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- 2017
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39. Protective effect of black tea extract against aluminium chloride-induced Alzheimer's disease in rats: A behavioural, biochemical and molecular approach
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Dhivya Bharathi Mathiyazahan, Arokiasamy Justin Thenmozhi, and Thamilarasan Manivasagam
- Subjects
Alzheimer's disease ,Aluminium chloride ,Black tea ,Memory ,Amyloid peptide ,Apoptosis ,Nutrition. Foods and food supply ,TX341-641 - Abstract
Aluminium is reported to play an important role in the aetiology, pathogenesis and development of Alzheimer's disease (AD). Black tea (BT, Camellia sinensis, family – Theaceae) represents approximately 78% of total consumed tea in the world and possesses neuroprotective properties under conditions like hypoxia, ischaemia and Parkinson's disease. This research aimed to evaluate neuroprotective effect of black tea extract (BTE) on the cognitive deficits, activity of acetylcholinesterase (AChE), levels and activities of oxidant–antioxidant indices (thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH), superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx)), expressions of β amyloid 1–42 (Aβ1–42) synthesis related (amyloid precursor protein (APP), β and γ secretases) and apoptotic markers (Bax, Bcl-2, cyto c, caspases 3, 8 and 9) in hippocampus and cortex of aluminium chloride (AlCl3) induced AD rats. Chronic AlCl3 administration (100 mg/kg body weight i.p.) in Wistar rats for 60 days significantly enhanced the AChE activity, memory impairment, oxidative damage, Aβ burden and apoptosis markers. Co-administration of BTE to AlCl3 rats for 60 days significantly ameliorated the aluminium induced pathological changes. Thus, it is suggested that the anti-Alzheimer role of BTE may be attributed mainly to the active components present in black tea.
- Published
- 2015
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40. Amyloid hexapeptide prevent dental caries by antibiofilm formation.
- Author
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Huang Y, Wang T, Chen Y, Lin H, and Chen D
- Subjects
- Animals, Rats, Male, Humans, Amyloid pharmacology, Cariostatic Agents pharmacology, X-Ray Microtomography, Rats, Sprague-Dawley, Streptococcus mutans, Biofilms, Dental Caries prevention & control, Dental Caries microbiology
- Abstract
Objectives: Biofilm formed by cariogenic microbes is the direct cause of dental caries, therefore, prevention of dental caries should be anti-biofilm-based. Previously, we found the amyloid hexapeptides efficiently inhibited biofilm formation by aggregating into amyloid fibrils agglutinating microbes. This study aimed to select the most stable amyloid hexapeptide GIDLKI (GI6) and study its anti-caries effect., Methods: Biofilms of multi-species bacteria, derived from mixed saliva, were cultured to evaluate the anti-biofilm formation effect of GI6. And then, the primary cariogenic bacterium Streptococcus mutans (S.mutans) was cultured in BHI with various pH, gradient concentrations of sucrose, glucose, and calcium ions to evaluate the anti-biofilm formation effects of GI6. Then models of human enamel block caries and twenty male SPF-SD rat caries induced by S. mutans biofilm were constructed, and confocal laser scanning microscopy, scanning electron microscopy, and micro-computed tomography were applied to investigate the anti-biofilm formation, anti-caries effects and use safety of GI6., Results: GI6 could inhibit the multi-species bacteria biofilm formation and remained effective in anti-biofilm activity against S. mutans in environments closely related to caries. GI6 suppressed S. mutans biofilm formation and thus prevented or alleviated the development of caries in human tooth blocks and rat teeth. GI6 did not affect the intestinal flora, serum biochemical parameters, and the pathological changes of various organs., Conclusions: Amyloid hexapeptides, including but not limited to GI6, are novel effective anti-caries agents that can be used to prevent dental caries safely., Clinical Significance: This study explored the anti-biofilm formation and anti-caries effect of GI6 in vitro, highlighting the anti-biofilm formation therapy for dental caries and setting a foundation for the practical application of GI6 for the treatment of dental caries., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowlegements This study was supported by the National Nature Science Foundation of China (no.82204253, no.81970928)., (Copyright © 2023. Published by Elsevier Ltd.)
- Published
- 2023
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41. Amyloid Peptide Pores and the Beta Sheet Conformation
- Author
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Kagan, Bruce L., Thundimadathil, Jyothi, Back, Nathan, editor, Cohen, Irun R., editor, Lajtha, Abel, editor, Lambris, John D., editor, Paoletti, Rodolfo, editor, Anderluh, Gregor, editor, and Lakey, Jeremy, editor
- Published
- 2010
- Full Text
- View/download PDF
42. Microencapsulated Choroid Plexus Epithelial Cell Transplants for Repair of the Brain
- Author
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Thanos, Christopher G., Bintz, Briannan, Emerich, Dwaine F., Back, Nathan, editor, Cohen, Irun R., editor, Lajtha, Abel, editor, Lambris, John D., editor, Paoletti, Rodolfo, editor, Pedraz, José Luis, editor, and Orive, Gorka, editor
- Published
- 2010
- Full Text
- View/download PDF
43. Overexpression of SNX3 Decreases Amyloid-β Peptide Production by Reducing Internalization of Amyloid Precursor Protein.
- Author
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Xu, Shaohua, Nigam, Saket M., and Brodin, Lennart
- Subjects
- *
SORTING nexins , *ALZHEIMER'S disease , *AMYLOID beta-protein , *AMYLOID beta-protein precursor , *SECRETASES , *PROTEIN expression , *PROTEIN-protein interactions , *BUNGAROTOXIN - Abstract
Sorting nexins (SNXs) have diverse functions in protein sorting and membrane trafficking. Recently, single-nucleotide polymorphisms in SNX3 were found to be associated with Alzheimer disease. However, it remains unknown whether SNX3 participates in amyloid (A)β peptide production.Background: To examine the role of SNX3 in Aβ production and APP processing.Objective: The effect of increased expression of SNX3 was studied in HEK293T cells. Aβ peptides were measured by immunoassay. Protein-protein association was analyzed by a bimolecular fluorescence complementation (BiFC) assay. APP uptake was measured with an α-bungarotoxin-binding assay, and flow cytometry was used to measure cell surface APP levels.Methods: We found that overexpression of SNX3 in HEK293T cells decreases the levels of secreted Aβ and soluble N-terminal APP fragments (sAPPβ). The reduction correlated with a decreased association of APP with BACE1, as revealed by BiFC. This effect may, in part, be explained by a reduced internalization of APP; SNX3 overexpression reduced APP internalization as determined by an α-bungarotoxin-binding assay, and caused increased APP levels on the cell surface, as shown by flow cytometry. In addition, SNX3 overexpression increased the cellular levels of full-length APP.Results: These results provide evidence that SNX3 regulates Aβ production by influencing the internalization of APP. [ABSTRACT FROM AUTHOR]Conclusion: - Published
- 2018
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44. Multivalent interacting glycodendrimer to prevent amyloid-peptide fibril formation induced by Cu(II): A multidisciplinary approach.
- Author
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Janaszewska, Anna, Klajnert-Maculewicz, Barbara, Marcinkowska, Monika, Duchnowicz, Piotr, Appelhans, Dietmar, Grasso, Gianvito, Deriu, Marco, Danani, Andrea, Cangiotti, Michela, and Ottaviani, Maria
- Abstract
Amyloid peptide fibrillogenesis induced by Cu(II) ions is a key event in the pathogenesis of Alzheimer's disease. Dendrimers have been found to be active in preventing fibril formation. Therefore, they hold promise for the treatment of Alzheimer's disease. In this study, the fibrillation mechanism of amyloid peptide Aβ 1-40 was studied by adding Cu(II) in the absence and presence of 4 generation poly(propyleneimine) glycodendrimer functionalized with sulfate groups, using dynamic light scattering (DLS), circular dichroism (CD), fluorescence, electron paramagnetic resonance (EPR) and molecular modeling (MD). The glycodendrimer was non-toxic to mHippoE-18 embryonic mouse hippocampal cells, selected as a nerve cell model, and decreased the toxicity of peptide aggregates formed after the addition of Cu(II). The binary systems of Cu(II)-glycodendrimer, Cu(II)-peptide, and glycodendrimer-peptide were first characterized. At the lowest Cu(II)/glycodendrimer molar ratios, Cu(II) was complexed by the internal-dendrimer nitrogen sites. After saturation of these sites, Cu(II) binding with sulfate groups occurred. Stable Cu(II)-peptide complexes formed within 5 min and were responsible for a transition from an α helix to a β-sheet conformation of Aβ 1-40. Glycodendrimer-peptide interactions provoked the stabilization of the α-helix, as demonstrated in the absence of Cu(II) by the Thioflavin T assay, and in the presence of Cu(II) by CD, EPR, and MD. Formation of fibrils is differentially modulated by glycodendrimer and Cu(II) concentrations for a fixed amount of Aβ 1-40. Therefore, this multidisciplinary study facilitated the recognition of optimal experimental conditions that allow the glycodendrimer to avoid the fibril formation induced by Cu(II). [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
45. Overexpression of SNX7 reduces Aβ production by enhancing lysosomal degradation of APP.
- Author
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Xu, Shaohua, Zhang, Lu, and Brodin, Lennart
- Subjects
- *
AMYLOID beta-protein precursor , *ALZHEIMER'S disease , *GENETIC overexpression , *SORTING nexins , *LYSOSOMES - Abstract
Abnormal production of amyloid-β peptides (Aβ) by proteolytic processing of amyloid precursor protein (APP) is thought to be central to the pathogenesis of Alzheimer's disease (AD). Although many efforts have been made to investigate mechanisms that regulate APP processing, many details remain incompletely understood. Sorting nexins (SNXs) are a family of proteins which are involved in many intracellular trafficking events. Several SNXs have been implicated in APP processing and Aβ production. In this study, we extended the investigation to SNX7. We found that overexpression of SNX7 in HEK293T cells reduces the levels of secreted Aβ and β-cleaved N-terminal APP fragments (sAPPβ). Moreover, SNX7 overexpression caused a significant reduction of the steady-state levels of APP as well as of the cell surface APP levels. By using NH 4 Cl and Bafilomycin A1 to inhibit the lysosomal degradative pathway, we found that the reduction of APP induced by SNX7 overexpression was prevented by such inhibition. No change in the cell surface distribution or steady-state levels of BACE1 was detected after overexpression of SNX7. Taken together, these results suggest that SNX7 regulates Aβ production by directing APP for degradation. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
46. Graphene oxide-iron oxide nanocomposite as an inhibitor of Aβ 42 amyloid peptide aggregation.
- Author
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Ahmad, Israr, Mozhi, Anbu, Yang, Lin, Han, Qiusen, Liang, Xingjie, Li, Chan, Yang, Rong, and Wang, Chen
- Subjects
- *
AMYLOID , *BIOLOGICAL aggregation , *SYNTHESIS of Nanocomposite materials , *CHEMICAL inhibitors , *GRAPHENE oxide - Abstract
Inhibiting amyloid β (Aβ) aggregation has drawn much attention because it is one of the main reasons for the cause of Alzheimer’s disease (AD). Here we have synthesized a nanocomposite of graphene oxide-iron oxide (GOIO) and demonstrated its ability of modulating Aβ aggregation. The inhibition effects of the GOIO nanocomposite on Aβ aggregates was studied by Thioflavin T fluorescence assay, circular dichroism and transmission electron microscopy, respectively. Furthermore, the cell viability study revealed that the GOIO nanocomposite can reduce the toxicity of Aβ fibrils to neuroblastoma cells. Our results demonstrated that the combination of GO and IO as a nanocomposite material has a potential use for the design new therapeutic agents for the treatment of Alzheimer’s disease. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
47. Cellular Membranes as Targets in Amyloid Oligomer Disease Pathogenesis
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Mina, Erene W., Glabe, Charles G., Bures, Jan, editor, Kopin, Irwin, editor, McEwen, Bruce, editor, Pribram, Karl, editor, Rosenblatt, Jay, editor, Weiskranz, Lawrence, editor, Fisher, Abraham, editor, Memo, Maurizio, editor, Stocchi, Fabrizio, editor, and Hanin, Israel, editor
- Published
- 2008
- Full Text
- View/download PDF
48. Aβ Variants and Their Impact on Amyloid Formation and Alzheimer’s Disease Progression
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Otvos, Laszlo, Jr., Barrow, Colin J., editor, and Small, David H., editor
- Published
- 2007
- Full Text
- View/download PDF
49. Protein Aggregation, Ion Channel Formation, and Membrane Damage
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Kagan, Bruce L., Atassi, M. Zouhair, editor, Berliner, Lawrence J., editor, Chang, Rowen Jui-Yoa, editor, Jörnvall, Hans, editor, Kenyon, Geroge L., editor, Wittman-Liebold, Brigitie, editor, Uversky, Vladimir N., editor, and Fink, Anthony L., editor
- Published
- 2006
- Full Text
- View/download PDF
50. Melatonin Efficacy to Treat Circadian Alterations of Sleep in Alzheimer’s Disease
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Cardinali, Daniel P., Furio, Analía M., Brusco, Luis I., Liberczuk, Cynthia, Lader, Malcolm, Cardinali, Daniel P., and Pandi-Perumal, S. R.
- Published
- 2006
- Full Text
- View/download PDF
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