scholarly journals Binding of Aβ to α- and β-synucleins: identification of segments in α-synuclein/NAC precursor that bind Aβ and NAC

1997 ◽  
Vol 323 (2) ◽  
pp. 539-546 ◽  
Author(s):  
Poul H. JENSEN ◽  
Peter HØJRUP ◽  
Henrik HAGER ◽  
Morten S. NIELSEN ◽  
Linda JACOBSEN ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Solid Phase ◽  
Amyloid Plaques ◽  
Binding Activity ◽  
Cross Linking ◽  
Spectrometric Analysis ◽  
Binding Domains ◽  
Aβ Fibrils

NAC, a 35-residue peptide derived from the neuronal protein α-synuclein/NAC precursor, is tightly associated with Aβ fibrils in Alzheimer's disease amyloid, and α-synuclein has recently been shown to bind Aβ in vitro. We have studied the interaction between Aβ and synucleins, aiming at determining segments in α-synuclein that can account for the binding, as well as identifying a possible interaction between Aβ and the β-type synuclein. We report that Aβ binds to native and recombinant α-synuclein, and to β-synuclein in an SDS-sensitive interaction (IC50 approx. 20 μM), as determined by chemical cross-linking and solid-phase binding assays. α-Synuclein and β-synuclein were found to stimulate Aβ-aggregation in vitro to the same extent. The synucleins also displayed Aβ-inhibitable binding of NAC and they were capable of forming dimers. Using proteolytic fragmentation of α-synuclein and cross-linking to 125I-Aβ, we identified two consecutive binding domains (residues 1–56 and 57–97) by Edman degradation and mass spectrometric analysis, and a synthetic peptide comprising residues 32–57 possessed Aβ-binding activity. To test further the possible significance in pathology, α-synuclein was biotinylated and shown to bind specifically to amyloid plaques in a brain with Alzheimer's disease. It is proposed that the multiple Aβ-binding sites in α-synuclein are involved in the development of amyloid plaques.

Synthesis of a Novel Curcumin Derivative as a Potential Imaging Probe in Alzheimer’s Disease Imaging

2019 ◽  
Vol 16 (8) ◽  
pp. 723-731 ◽  
Author(s):  
Alexander Sturzu ◽  
Sumbla Sheikh ◽  
Hubert Kalbacher ◽  
Thomas Nägele ◽  
Christopher Weidenmaier ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Flow Cytometry ◽  
Transgenic Mice ◽  
Ex Vivo ◽  
Amyloid Plaques ◽  
Laser Scanning Microscopy ◽  
Β Amyloid ◽  
Curcumin Derivative

Background: Curcumin has been of interest in the field of Alzheimer’s disease. Early studies on transgenic mice showed promising results in the reduction of amyloid plaques.However, curcumin is very poorly soluble in aqueous solutions and not easily accessible to coupling as it contains only phenolic groups as potential coupling sites. For these reasons only few imaging studies using curcumin bound as an ester were performed and curcumin is mainly used as nutritional supplement. Methods: In the present study we produced an aminoethyl ether derivative of curcumin using a nucleophilic substitution reaction. This is a small modification and should not impact the properties of curcumin while introducing an easily accessible reactive amino group. This novel compound could be used to couple curcumin to other molecules using the standard methods of peptide synthesis. We studied the aminoethyl-curcumin compound and a tripeptide carrying this aminoethyl-curcumin and the fluorescent dye fluorescein (FITC-curcumin) in vitro on cell culture using confocal laser scanning microscopy and flow cytometry. Then these two substances were tested ex vivo on brain sections prepared from transgenic mice depicting Alzheimer-like β-amyloid plaques. Results: In the in vitro CLSM microscopy and flow cytometry experiments we found dot-like unspecific uptake and only slight cytotoxicity correlating with this uptake. As these measurements were optimized for the use of fluorescein as dye we found that the curcumin at 488nm fluorescence excitation was not strong enough to use it as a fluorescence marker in these applications. In the ex vivo sections CLSM experiments both the aminoethyl-curcumin and the FITC-curcumin peptide bound specifically to β- amyloid plaques. Conclusion: In conclusion we successfully produced a novel curcumin derivative which could easily be coupled to other imaging or therapeutic molecules as a sensor for amyloid plaques.

P2-014: In vitro study on Pittsburgh Compound-B (PIB) binding to brain amyloid plaques in mouse models of Alzheimer's Disease (AD)

2011 ◽  
Vol 7 ◽  
pp. S311-S311
Author(s):  
Zhizhen Zeng ◽  
Tsing-Bau Chen ◽  
Brett Connolly ◽  
Patricia Miller ◽  
Stacey O'Malley ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
In Vitro Study ◽  
Amyloid Plaques ◽  
Vitro Study ◽  
Pittsburgh Compound B

scholarly journals Porphyromonas gingivalis is a Strong Risk Factor for Alzheimer’s Disease

2020 ◽  
Vol 4 (1) ◽  
pp. 501-511
Author(s):  
Shalini Kanagasingam ◽  
Sasanka S. Chukkapalli ◽  
Richard Welbury ◽  
Sim K. Singhrao
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Porphyromonas Gingivalis ◽  
Bacterial Load ◽  
Amyloid Β ◽  
Wild Type Mouse ◽  
Paired Helical Filaments ◽  
Binding Domains ◽  
Flanking Regions

Porphyromonas gingivalis (P. gingivalis) is one of the several important bacterial pathogens associated with the sporadic Alzheimer’s disease (AD). Different serotypes are either capsulated or are non-capsulated. It has been demonstrated that P. gingivalis (non-capsulated) can reproduce the neurodegenerative AD-like changes in vitro, and a capsular P. gingivalis (strain W83) could reproduce the cardinal hallmark lesions of AD in a wild-type mouse model. All P. gingivalis forms express proteolytically active proteases that enable cleavage of the amyloid-β protin precursor (AβPP) and tau resulting in the formation of amyloid-β and neurofibrillary tangles. Tau is an established substrate for gingipains, which can cleave tau into various peptides. Some of the P. gingivalis fragmented tau protein peptides contain “VQIINK” and “VQIVYK” hexapeptide motifs which map to the flanking regions of the microtubule binding domains and are also found in paired helical filaments that form NFTs. P. gingivalis can induce peripheral inflammation in periodontitis and can also initiate signaling pathways that activate kinases, which in turn, phosphorylate neuronal tau. Periodontal disease related inflammation has metabolic implications for an individual’s peripheral and brain health as patients suffering from generalized periodontitis often have related co-morbidities and are “at risk” of developing AD. The aim here is to discuss the role of P. gingivalis behind such associations with the backdrop of huge efforts to test P. gingivalis virulence factors clinically (GAIN Trial: Phase 2/3 Study of COR388 in Subjects with AD) with inhibitors, which may lead to an intervention by reducing the pathogenic bacterial load.

scholarly journals Modulation of β-Amyloid Fibril Formation in Alzheimer’s Disease by Microglia and Infection

2020 ◽  
Vol 13 ◽  
Author(s):  
Madeleine R. Brown ◽  
Sheena E. Radford ◽  
Eric W. Hewitt
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Fibril ◽  
Amyloid Β ◽  
Aβ Peptides ◽  
Aβ Amyloid ◽  
Aβ Fibrils ◽  
The Brain

Amyloid plaques are a pathological hallmark of Alzheimer’s disease. The major component of these plaques are highly ordered amyloid fibrils formed by amyloid-β (Aβ) peptides. However, whilst Aβ amyloid fibril assembly has been subjected to detailed and extensive analysis in vitro, these studies may not reproduce how Aβ fibrils assemble in the brain. This is because the brain represents a highly complex and dynamic environment, and in Alzheimer’s disease multiple cofactors may affect the assembly of Aβ fibrils. Moreover, in vivo amyloid plaque formation will reflect the balance between the assembly of Aβ fibrils and their degradation. This review explores the roles of microglia as cofactors in Aβ aggregation and in the clearance of amyloid deposits. In addition, we discuss how infection may be an additional cofactor in Aβ fibril assembly by virtue of the antimicrobial properties of Aβ peptides. Crucially, by understanding the roles of microglia and infection in Aβ amyloid fibril assembly it may be possible to identify new therapeutic targets for Alzheimer’s disease.

scholarly journals Modified Low-Temperature Extraction Method for Isolation of Bletilla striata Polysaccharide as Antioxidant for the Prevention of Alzheimer’s Disease

2021 ◽  
Vol 22 (23) ◽  
pp. 12760
Author(s):  
Yi-Wen Lin ◽  
Chih-Hsiang Fang ◽  
Ya-Jyun Liang ◽  
Hong-Hsiang Liao ◽  
Feng-Huei Lin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Low Temperature ◽  
Amyloid Β ◽  
Bletilla Striata ◽  
Modified Method ◽  
Temperature Method ◽  
Aβ Fibrils

Amyloid-β (Aβ) peptides play a key role in Alzheimer’s disease (AD), the most common type of dementia. In this study, a polysaccharide from Bletilla striata (BSP), with strong antioxidant and anti-inflammatory properties, was extracted using a low-temperature method and tested for its efficacy against AD, in vitro using N2a and BV-2 cells, and in vivo using an AD rat model. The characterization of the extracted BSP for its molecular structure and functional groups demonstrated the effectiveness of the modified method for retaining its bioactivity. In vitro, BSP reduced by 20% reactive oxygen species (ROS) levels in N2a cells (p = 0.0082) and the expression levels of inflammation-related genes by 3-fold TNF-α (p = 0.0048), 4-fold IL-6 (p = 0.0019), and 2.5-fold IL-10 (p = 0.0212) in BV-2 cells treated with Aβ fibrils. In vivo, BSP recovered learning memory, ameliorated morphological damage in the hippocampus and cortex, and reduced the expression of the β-secretase protein in AlCl3-induced AD rats. Collectively, these findings demonstrated the efficacy of BSP for preventing and alleviating the effects of AD.

scholarly journals A Peptide-Based Nanocarrier for an Enhanced Delivery and Targeting of Flurbiprofen into the Brain for the Treatment of Alzheimer’s Disease: An In Vitro Study

Nanomaterials ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 1590
Author(s):  
Shafq Al-azzawi ◽  
Dhafir Masheta ◽  
Anna Guildford ◽  
Gary Phillips ◽  
Matteo Santin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
High Efficiency ◽  
Solid Phase ◽  
Amyloid Β ◽  
In Vitro Study ◽  
Target Cells ◽  
Age Related ◽  
The Brain

Alzheimer’s disease (AD) is an age-related disease caused by abnormal accumulation of amyloid-β in the brain leading to progressive tissue degeneration. Flurbiprofen (FP), a drug used to mitigate the disease progression, has low efficacy due to its limited permeability across the blood–brain barrier (BBB). In a previous work, FP was coupled at the uppermost branching of an ε-lysine-based branched carrier, its root presenting a phenylalanine moiety able to increase the hydrophobicity of the complex and enhance the transport across the BBB by adsorptive-mediated transcytosis (AMT). The present study explores a different molecular design of the FP-peptide delivery system, whereby its root presents an ApoE-mimicking peptide, a targeting ligand that could enhance transport across the BBB by receptor-mediated transcytosis (RMT). The functionalised complex was synthesised using a solid-phase peptide synthesis and characterised by mass spectrometry and FTIR. Cytotoxicity and permeability of this complex across an in vitro BBB model were analysed. Moreover, its activity and degradation to release the drug were investigated. The results revealed successful synthesis and grafting of FP molecules at the uppermost molecular branches of the lysine terminal without observed cytotoxicity. When covalently linked to the nanocarrier, FP was still active on target cells, albeit with a reduced activity, and was released as a free drug upon hydrolysis in a lysosome-mimicking medium. Noticeably, this work shows the high efficiency of RMT-driven FP delivery over delivery systems relying on AMT.

scholarly journals Nanoparticulate Radiolabelled Quinolines Detect Amyloid Plaques in Mouse Models of Alzheimer's Disease

2009 ◽  
Vol 2009 ◽  
pp. 1-8 ◽  
Author(s):  
Celeste A. Roney ◽  
Veera Arora ◽  
Padmakar V. Kulkarni ◽  
Peter P. Antich ◽  
Frederick J. Bonte
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Mouse Models ◽  
Amyloid Plaques ◽  
Brain Uptake ◽  
Amyloid Peptides ◽  
Storage Phosphor

Detecting aggregated amyloid peptides (Aβplaques) presents targets for developing biomarkers of Alzheimer's disease (AD). Polymeric n-butyl-2-cyanoacrylate (PBCA) nanoparticles (NPs) were encapsulated with radiolabelled amyloid affinityI125-clioquinol (CQ, 5-chloro-7-iodo-8-hydroxyquinoline) as in vivo probes.I125-CQ-PBCA NPs crossed the BBB (2.3±0.9 ID/g) (P<.05) in the WT mouse (N= 210), compared toI125-CQ (1.0±0.4 ID/g).I125-CQ-PBCA NP brain uptake increased in AD transgenic mice (APP/PS1) versus WT (N= 38;2.54×105±5.31×104 DLU/mm2; versus1.98×105±2.22×104 DLU/mm2) and in APP/PS1/Tau. Brain increases were in mice intracranially injected with aggregated Aβ42peptide (N= 17;7.19×105±1.25×105 DLU/mm2), versus WT (6.07×105±7.47×104 DLU/mm2). Storage phosphor imaging and histopathological staining of the plaques,Fe2+andCu2+, validated results.I125-CQ-PBCA NPs have specificity for Aβin vitro and in vivo and are promising as in vivo SPECT (I123), or PET (I124) amyloid imaging agents.

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