Protein Capped Metal Nanoparticles Inhibits Tau Aggregation in Alzheimer’s Disease

2019 ◽  
Author(s):  
Absar Ahmad ◽  
Subashchandrabose Chinnathambi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Metal Nanoparticles ◽  
Neuroblastoma Cells ◽  
Cadmium Sulphide ◽  
Cds Nanoparticles ◽  
Aggregation Inhibitors ◽  
Therapeutic Research ◽  
Tau Aggregation

The Alzheimer’s disease (AD) therapeutic research is yielding large number of potent molecules. The nanoparticle-based therapeutics against the protein aggregation in AD is also taking a lead especially with amyloid beta as a primary target. In this work, we have screened for first time, the protein capped (PC) metal nanoparticles for their potency in inhibiting Tau aggregation in vitro. We present a novel function of PC-CdS nanoparticles as a potent Tau aggregation inhibitor by fluorescence spectrometry, SDS-PAGE and Electron microscopy. We demonstrate that the biologically synthesized PC-metal nanoparticles, iron oxide and cadmium sulphide do not affect the viability of neuroblastoma cells. Moreover, PC-CdS nanoparticles show dual property of inhibition as well as disaggregation of Tau. Thus, the nanoparticles can take a lead as potent Tau aggregation inhibitors and can be modified for specific drug delivery due to very small size. This current work presents unprecedented strategy to design anti-Tau aggregation drugs, which provides interesting insights to understand the role of biological nanostructures in Alzheimer’s disease.

Protein Capped Metal Nanoparticles Inhibits Tau Aggregation in Alzheimer’s Disease

2019 ◽  
Author(s):  
Absar Ahmad ◽  
Subashchandrabose Chinnathambi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Metal Nanoparticles ◽  
Neuroblastoma Cells ◽  
Cadmium Sulphide ◽  
Cds Nanoparticles ◽  
Aggregation Inhibitors ◽  
Therapeutic Research ◽  
Tau Aggregation

The Alzheimer’s disease (AD) therapeutic research is yielding large number of potent molecules. The nanoparticle-based therapeutics against the protein aggregation in AD is also taking a lead especially with amyloid beta as a primary target. In this work, we have screened for first time, the protein capped (PC) metal nanoparticles for their potency in inhibiting Tau aggregation in vitro. We present a novel function of PC-CdS nanoparticles as a potent Tau aggregation inhibitor by fluorescence spectrometry, SDS-PAGE and Electron microscopy. We demonstrate that the biologically synthesized PC-metal nanoparticles, iron oxide and cadmium sulphide do not affect the viability of neuroblastoma cells. Moreover, PC-CdS nanoparticles show dual property of inhibition as well as disaggregation of Tau. Thus, the nanoparticles can take a lead as potent Tau aggregation inhibitors and can be modified for specific drug delivery due to very small size. This current work presents unprecedented strategy to design anti-Tau aggregation drugs, which provides interesting insights to understand the role of biological nanostructures in Alzheimer’s disease.

scholarly journals Peptide-based inhibitors of Tau aggregation as a potential therapeutic for Alzheimer's disease and other Tauopathies

2021 ◽  
Author(s):  
Anthony Aggidis ◽  
Shreyasi Chatterjee ◽  
David Townsend ◽  
Nigel J Fullwood ◽  
Eva Ruiz Ortega ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hek 293 ◽  
293 Cells ◽  
Aggregation Inhibitors ◽  
Behavioural Phenotypes ◽  
Tau Aggregation ◽  
Transgenic Drosophila

There are currently no disease altering drugs available for Tauopathies such as Alzheimer's disease, which alone is predicted to affect ~88 million people worldwide by 2050. As Tau aggregation underpins its toxicity, aggregation inhibitors are likely to have disease-modifying potential. Guided by in-silico mutagenesis studies, we developed a potent retro-inverso peptide inhibitor of Tau aggregation, RI-AG03 [AcrrrrrrrrGpkyk( ac)iqvGr-NH2], based on the 306VQIVYK311 hotspot. Aggregation of recombinant Tau was reduced by >90% with equimolar RI-AG03 and no fibrils were observed by EM. When added during the growth phase, RI-AG03 blocked seeded aggregation. Fluorescein-tagged RI-AG03 efficiently penetrated HEK-293 cells over 24 hours and was non-toxic at doses up to 30 μM. In transgenic Drosophila, RI-AG03 significantly improves neurodegenerative and behavioural phenotypes caused by expression of human Tau. Collectively this shows that RI-AG03 can effectively reduce Tau aggregation in vitro and block aggregationdependent phenotypes in vivo, raising possibilities for exploring its translational potential.

scholarly journals Arrayed CRISPR reveals genetic regulators of tau aggregation, autophagy and mitochondria in Alzheimer’s disease model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lishu Duan ◽  
Mufeng Hu ◽  
Joseph A. Tamm ◽  
Yelena Y. Grinberg ◽  
Fang Shen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Discovery ◽  
Disease Model ◽  
Mitochondrial Morphology ◽  
Individual Gene ◽  
Human Genes ◽  
Future Drug ◽  
Tau Aggregation

AbstractAlzheimer’s disease (AD) is a common neurodegenerative disease with poor prognosis. New options for drug discovery targets are needed. We developed an imaging based arrayed CRISPR method to interrogate the human genome for modulation of in vitro correlates of AD features, and used this to assess 1525 human genes related to tau aggregation, autophagy and mitochondria. This work revealed (I) a network of tau aggregation modulators including the NF-κB pathway and inflammatory signaling, (II) a correlation between mitochondrial morphology, respiratory function and transcriptomics, (III) machine learning predicted novel roles of genes and pathways in autophagic processes and (IV) individual gene function inferences and interactions among biological processes via multi-feature clustering. These studies provide a platform to interrogate underexplored aspects of AD biology and offer several specific hypotheses for future drug discovery efforts.

scholarly journals Design, Synthesis, and In Vitro Evaluation of Hydroxybenzimidazole-Donepezil Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer’s Disease

Molecules ◽  
2020 ◽  
Vol 25 (4) ◽  
pp. 985 ◽  
Author(s):  
Sílvia Chaves ◽  
Simonetta Resta ◽  
Federica Rinaldo ◽  
Marina Costa ◽  
Romane Josselin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuroblastoma Cells ◽  
Biological Properties ◽  
Design Synthesis ◽  
Aβ Aggregation ◽  
Structural Isomerization ◽  
Good Potential ◽  
Nitro Derivatives

A series of multi-target-directed ligands (MTDLs), obtained by attachment of a hydroxyphenylbenzimidazole (BIM) unit to donepezil (DNP) active mimetic moiety (benzyl-piperidine/-piperazine) was designed, synthesized, and evaluated as potential anti-Alzheimer’s disease (AD) drugs in terms of biological activity (inhibition of acetylcholinesterase (AChE) and β–amyloid (Aβ) aggregation), metal chelation, and neuroprotection capacity. Among the DNP-BIM hybrids studied herein, the structural isomerization did not significantly improve the biological properties, while some substitutions, namely fluorine atom in each moiety or the methoxy group in the benzyl ring, evidenced higher cholinergic AChE activity. All the compounds are able to chelate Cu and Zn metal ions through their bidentate BIM moieties, but compound 5, containing a three-dentate chelating unit, is the strongest Cu(II) chelator. Concerning the viability on neuroblastoma cells, compounds 9 and 10 displayed the highest reduction of Aβ-induced cell toxicity. In silico calculations of some pharmacokinetic descriptors indicate that all the compounds but the nitro derivatives have good potential oral-bioavailability. Overall, it can be concluded that most of the studied DNP-BIM conjugates showed quite good anti-AD properties, therefore deserving to be considered in further studies with the aim of understanding and treating AD.

Bioavailability and Pharmaco-therapeutic Potential of Luteolin in Overcoming Alzheimer’s Disease

2019 ◽  
Vol 18 (5) ◽  
pp. 352-365 ◽  
Author(s):  
Fahad Ali ◽  
Yasir Hasan Siddique
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Potential ◽  
In Vivo Models ◽  
Naturally Occurring ◽  
Current Review ◽  
Tau Aggregation ◽  
Dose Limiting Toxicity

Luteolin is a naturally occurring, yellow crystalline flavonoid found in numerous dietary supplements we frequently have in our meals. Studies in the last 2 decades have revealed its therapeutic potential to reduce the Alzheimer’s disease (AD) symptoms in various in vitro and in vivo models. The anti-Alzheimer’s potential of luteolin is attributed to its ability to suppress Aβ as well as tau aggregation or promote their disaggregation, down-regulate the expression of COX-2, NOS, MMP-9, TNF-α, interleukins and chemokines, reduce oxidative stress by scavenging ROS, modulate the activities of transcription factors CREB, cJun, Nrf-1, NF-κB, p38, p53, AP-1 and β-catenine and inhibiting the activities of various protein kinases. In several systems, luteolin has been described as a potent antioxidant and anti-inflammatory agent. In addition, we have also discussed about the bio-availability of the luteolin in the plasma. After being metabolized luteolin persists in plasma as glucuronides and sulphate-conjugates. Human clinical trials indicated no dose limiting toxicity when administered at a dose of 100 mg/day. Improvements in the formulations and drug delivery systems may further enhance the bioavailability and potency of luteolin. The current review describes in detail the data supporting these studies.

scholarly journals Comparative Neuroprotective Effects of Dietary Curcumin and Solid Lipid Curcumin Particles in Cultured Mouse Neuroblastoma Cells after Exposure to Aβ42

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Panchanan Maiti ◽  
Gary L. Dunbar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Survival ◽  
Apoptotic Cell ◽  
Neuroblastoma Cells ◽  
Neuroprotective Effects ◽  
Solid Lipid ◽  
Mouse Neuroblastoma ◽  
Phosphorylated Akt

Aggregation of amyloid beta protein (Aβ) and phosphorylated tau (p-Tau) plays critical roles in pathogenesis of Alzheimer’s disease (AD). As an antiamyloid natural polyphenol, curcumin (Cur) has a potential role in prevention of neurodegeneration in AD. However, due to limited absorption of the dietary Cur, the solid lipid Cur particles (SLCP) have been suggested as being more effective for AD therapy. In the present study, we compared the role of dietary Cur and SLCP on oxidative stress, neuronal death, p-Tau level, and certain cell survival markers in vitro, after exposure to Aβ42. Mouse neuroblastoma cells were exposed to Aβ42 for 24 h and incubated with or without dietary Cur and/or SLCP. Reactive oxygen species (ROS), apoptotic cell death, p-Tau, and tau kinase (including GSK-3β and cell survival markers, such as total Akt, phosphorylated Akt, and PSD95 levels) were investigated. SLCP showed greater permeability than dietary Cur in vitro, decreased ROS production, and prevented apoptotic death. In addition, SLCP also inhibited p-Tau formation and significantly decreased GSK-3β levels. Further, the cell survival markers, such as total Akt, p-Akt, and PSD95 levels, were more effectively maintained by SLCP than dietary Cur in Aβ42 exposed cells. Therefore, SLCP may provide greater neuroprotection than dietary Cur in Alzheimer’s disease.

Development of Tau Aggregation Inhibitors for Alzheimer's Disease

2009 ◽  
Vol 48 (10) ◽  
pp. 1740-1752 ◽  
Author(s):  
Bruno Bulic ◽  
Marcus Pickhardt ◽  
Boris Schmidt ◽  
Eva-Maria Mandelkow ◽  
Herbert Waldmann ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Aggregation Inhibitors ◽  
Tau Aggregation

scholarly journals Astrocytic expression of the Alzheimer’s disease risk allele, ApoEε4, potentiates neuronal tau pathology in multiple preclinical models

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Angela Marie Jablonski ◽  
Lee Warren ◽  
Marija Usenovic ◽  
Heather Zhou ◽  
Jonathan Sugam ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Risk ◽  
In Vitro Models ◽  
Tau Pathology ◽  
Adeno Associated Virus ◽  
Human Apoe ◽  
Specific Effects ◽  
Tau Aggregation

AbstractApoEε4 is a major genetic risk factor for Alzheimer’s disease (AD), a disease hallmarked by extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). The presence of the ApoEε4 allele is associated with increased Aβ deposition and a role for ApoEε4 in the potentiation of tau pathology has recently emerged. This study focused on comparing the effects of adeno-associated virus (AAV)-mediated overexpression of the three predominant human ApoE isoforms within astrocytes. The isoform-specific effects of human ApoE were evaluated within in vitro models of tau pathology within neuron/astrocyte co-cultures, as well as in a transgenic tau mouse model. Tau aggregation, accumulation, and phosphorylation were measured to determine if the three isoforms of human ApoE had differential effects on tau. Astrocytic overexpression of the human ApoEε4 allele increased phosphorylation and misfolding of overexpressed neuronal tau in multiple models, including the aggregation and accumulation of added tau oligomers, in an isoform-specific manner. The ability of ApoEε4 to increase tau aggregation could be inhibited by an ApoEε4-specific antibody. This study indicates that astrocytic expression of ApoEε4 can potentiate tau aggregation and phosphorylation within neurons and supports a gain of toxic function hypothesis for the effect of hApoEε4 on tau.

Cinnamon Extract Inhibits Tau Aggregation Associated with Alzheimer's Disease In Vitro

2009 ◽  
Vol 17 (3) ◽  
pp. 585-597 ◽  
Author(s):  
Dylan W. Peterson ◽  
Roshni C. George ◽  
Francesca Scaramozzino ◽  
Nichole E. LaPointe ◽  
Richard A. Anderson ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cinnamon Extract ◽  
Tau Aggregation

scholarly journals Baicalein suppresses Tau fibrillization by sequestering oligomers

2019 ◽  
Author(s):  
Shweta Kishor Sonawane ◽  
Abhishek Ankur Balmik ◽  
Debjyoti Boral ◽  
Sureshkumar Ramasamy ◽  
Subashchandrabose Chinnathambi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Misfolding ◽  
Natural Compound ◽  
Neurodegenerative Disorder ◽  
Chinese Herb ◽  
Tau Oligomers ◽  
Aggregation Inhibitors ◽  
The Brain

Abstract Alzheimer’s disease (AD) is a neurodegenerative disorder caused by protein misfolding, aggregation and accumulation in the brain. A large number of molecules are being screened against these pathogenic proteins but the focus for therapeutics is shifting towards the natural compounds as aggregation inhibitors, mainly due to their minimum adverse effects. Baicalein is a natural compound belonging to the class of flavonoids isolated from the Chinese herb Scutellaria baicalensis. Here we applied fluorescence, absorbance, microscopy, MALDI-TOF spectrophotometry and other biochemical techniques to investigate the interaction between Tau and Baicalein in vitro. We found the aggregation inhibitory properties of Baicalein for the repeat Tau. Overall, the potential of Baicalein in dissolving the preformed Tau oligomers as well as mature fibrils can be of utmost importance in therapeutics for Alzheimer’s disease.

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