Journal articles: 'Amyloid-beta peptide (A-beta)'

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Buneeva, O. A., O. V. Gnedenko, M. V. Medvedeva, A. S. Ivanov, and A. E. Medvedev. "The effect of neuroprotector isatin on binding of some model proteins with beta-amyloid peptide: a biosensor study." Biomeditsinskaya Khimiya 62, no. 6 (2016): 720–24. http://dx.doi.org/10.18097/pbmc20166206720.

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The amyloid-beta peptide 1-42 formed during proteolytic processing of the amyloid precursor protein (APP) plays a key role in the development or progression of Alzheimer's disease (AD) and other pathologies associated with formation of protein aggregates in the central nervous system. Recent proteomic profiling of mouse and rat brain preparations by means of beta-amyloid peptide immobilized on Affigel-10 revealed a large group of amyloid-binding proteins (n>80). Many (about 25%) of these proteins were previously identified as isatin-binding proteins. The aim of this study was to validate direct interaction between beta-amyloid peptide and highly purified intact and oxidized peroxiredoxin, M-type pyruvate kinase, alpha-enolase, and the effect of isatin on this interaction. The study performed using SPR-based Biacore 3000 and Biacore X100 biosensors has shown that all the proteins form molecular complexes with immobilized beta-amyloid peptide. The Kd values for these complexes varied from 8.36х10^-8 M (peroxiredoxin) to 1.97х10^-6 M (alpha-enolase). Oxidative modification of investigated proteins caused opposite effects on complexes of these peptides with beta-amyloid. The endogenous neuroprotector isatin increased dissociation of complexes formed by beta-amyloid peptide with both intact proteins (peroxiredoxin, glyceraldehyde-3-phosphate dehydrogenase) and/or oxidized proteins (peroxiredoxin, pyruvate kinase) used in this study.

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Aloufi, Bandar. "Molecular dynamics simulation analysis of the beta amyloid peptide with docked inhibitors." Bioinformation 18, no. 7 (July 31, 2022): 622–29. http://dx.doi.org/10.6026/97320630018622.

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Beta amyloid peptide is widely studied due to its association with Alzheimer disease (AD). Various study reported that the accumulation of beta amyloid in brain cells leads to Alzheimer disease. Hence, Beta amyloid peptide could be a potential target of anti-AD therapy. Hence, it is of interest to develop potent inhibitors for Beta amyloid peptide in the context of Alzheimer disease (AD). We report the binding features of Ascorbic acid, Cysteine, Dithioerythriol, Dithiothreitol, Malic acid and α-Tocopherol with beta amyloid having binding energy values of -6.7, -6.5, -6.0, -6.5, -6.7 and - 7.0 kcal/mol respectively. The molecular docking of top-scoring compounds with beta amyloid suggests that amino acids such as ASP23, GLU22, Phe19, are crucial in binding. Molecular dynamics simulation study showed steady-state interaction of compounds with beta amyloid for further consideration.

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Uéda, K., H. Fukushima, E. Masliah, Y. Xia, A. Iwai, M. Yoshimoto, D. A. Otero, J. Kondo, Y. Ihara, and T. Saitoh. "Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease." Proceedings of the National Academy of Sciences 90, no. 23 (December 1, 1993): 11282–86. http://dx.doi.org/10.1073/pnas.90.23.11282.

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A neuropathological hallmark of Alzheimer disease (AD) is a widespread amyloid deposition. We analyzed the entire amino acid sequences in an amyloid preparation and found, in addition to the major beta/A4-protein (A beta) fragment, two unknown peptides. We raised antibodies against synthetic peptides using subsequences of these peptides. These antibodies immunostained amyloid in neuritic and diffuse plaques as well as vascular amyloid. Electron microscopic analysis demonstrated that the immunostaining was localized on amyloid fibrils. We have isolated an apparently full-length cDNA encoding a 140-amino-acid protein within which two previously unreported amyloid sequences are encoded in tandem in the most hydrophobic domain. We tentatively named this 35-amino acid peptide NAC (non-A beta component of AD amyloid) and its precursor NACP. NAC is the second component, after A beta, identified chemically in the purified AD amyloid preparation. Secondary structure predictions indicate that the NAC peptide sequence has a strong tendency to form beta-structures consistent with its association with amyloid. NACP is detected as a M(r) 19,000 protein in the cytosolic fraction of brain homogenates and comigrates on immunoblots with NACP synthesized in Escherichia coli from NACP cDNA. NACP mRNA is expressed principally in brain but is also expressed in low concentrations in all tissues examined except in liver, suggesting its ubiquitous and brain-specific functions. The availability of the cDNA encoding full-length NACP should help to elucidate the mechanisms of amyloidosis in AD.

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Jiang, H., D. Burdick, C. G. Glabe, C. W. Cotman, and A. J. Tenner. "beta-Amyloid activates complement by binding to a specific region of the collagen-like domain of the C1q A chain." Journal of Immunology 152, no. 10 (May 15, 1994): 5050–59. http://dx.doi.org/10.4049/jimmunol.152.10.5050.

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Abstract beta-amyloid peptides that accumulate within the brain of individuals with Alzheimer's disease bind to C1q and activate the classical C pathway via a specific interaction with a site within the collagen-like domain of C1q (C1q-CLF). Synthetic analogues of beta-amyloid peptides, beta 1-42 and beta 1-40, bound to C1q and were strong activators of C as assessed by both total C consumption and C4 consumption. beta 1-42 was significantly more effective than beta 1-40 in binding to C1q and triggering C activation, whereas beta 1-28 demonstrated little or no binding or C activation. This C-activating capacity seems to be largely correlated with the assembly of the beta 1-42 into low speed sedimentable aggregates and/or macromolecular fibrils. Radiolabeled C1q and C1q-CLF bind specifically to these aggregates or amyloid fibrils. In addition, using synthetic C1q peptides in a solid phase binding assay, the major binding site of beta 1-42 to C1q was localized to the C1q A chain collagen-like residues 14-26, a region previously described as a novel interaction site for Ab-independent activators of C1. C1q A chain peptide 14-26 blocked the ability of beta-amyloid peptides to activate the classical C pathway, providing evidence that this relatively unrecognized mechanism of C activation (via binding to the C1q-CLF) may have crucial physiologic consequences. Finally, these observations provide further support for the hypothesis that C activation and inflammation may be a component in the pathogenesis of AD and suggest possibilities for modulating the progression of AD.

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Klunk, W. E., J. W. Pettegrew, and D. J. Abraham. "Quantitative evaluation of congo red binding to amyloid-like proteins with a beta-pleated sheet conformation." Journal of Histochemistry & Cytochemistry 37, no. 8 (August 1989): 1273–81. http://dx.doi.org/10.1177/37.8.2666510.

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The binding of Congo red to several purified amyloid-like peptides having a beta-pleated sheet conformation was quantitatively examined. Congo red binds preferentially to the beta-pleated sheet conformation of both insulin fibrils and poly-L-lysine. Congo red does not bind nearly so well to poly-L-serine or polyglycine, despite the fact that these peptides also have a beta-pleated sheet conformation. Binding to insulin fibrils was saturable with an apparent Bmax of 2 moles of Congo red per mole of insulin fibrils and an apparent KD of 1.75 x 10(-7) M. Binding to beta-poly-L-lysine was similar but had a much higher apparent Bmax of 43. Binding of Congo red to beta-poly-L-lysine was pH dependent and appeared to be determined by the number of protonated lysine residues in the 250 amino acid peptide. We present a new hypothesis in which Congo red binds to amyloid-like proteins via bonds between the two negatively charged sulfonic acid groups of Congo red and two positively charged amino acid residues of two separate protein molecules which are properly oriented by virtue of the beta-pleated sheet conformation of the peptide backbone.

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Jensen, P. H., E. S. Sørensen, T. E. Petersen, J. Gliemann, and L. K. Rasmussen. "Residues in the synuclein consensus motif of the α-synuclein fragment, NAC, participate in transglutaminase-catalysed cross-linking to Alzheimer-disease amyloid βA4 peptide." Biochemical Journal 310, no. 1 (August 15, 1995): 91–94. http://dx.doi.org/10.1042/bj3100091.

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The widespread deposition of amyloid plaques is one of the hallmarks of Alzheimer disease (AD). A recently described component of amyloid plaques is the 35-residue peptide, non-A beta component of AD amyloid, which is derived from a larger intracellular neuronal constituent, alpha-synuclein. We demonstrate that transglutaminase catalyses the formation of the covalent non-A beta component of AD amyloid polymers in vitro as well as polymers with beta-amyloid peptide, the major constituent of AD plaques. The transglutaminase-reactive amino acid residues in the non-A beta component of AD amyloid were identified as Gln79 and Lys80. Lys80 is localized in a consensus motif Lys-Thr-Lys-Glu-Gly-Val, which is conserved in the synuclein gene family. Thus transglutaminase might be involved in the formation of insoluble amyloid deposits and participate in the modification of other members of the synuclein family.

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Usui, Kenji, Shin-ichiro Yokota, Kazuya Iwata, and Yoshio Hamada. "Novel Purification Process for Amyloid Beta Peptide(1-40)." Processes 8, no. 4 (April 15, 2020): 464. http://dx.doi.org/10.3390/pr8040464.

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Amyloid beta peptide (Aβ)-related studies require an adequate supply of purified Aβ peptide. However, Aβ peptides are “difficult sequences” to synthesize chemically, and low yields are common due to aggregation during purification. Here, we demonstrate an easier synthesis, deprotection, reduction, cleavage, and purification process for Aβ(1-40) using standard 9-fluorenylmethyloxycarbonyl (Fmoc)-protected amino acids and solid-phase peptide synthesis (SPPS) resin [HMBA (4-hydroxymethyl benzamide) resin] that provides higher yields of Aβ(1-40) than previous standard protocols. Furthermore, purification requires a similar amount of time as conventional purification processes, although the peptide must be cleaved from the resin immediately prior to purification. The method described herein is not limited to the production of Aβ(1-40), and can be used to synthesize other easily-oxidized and aggregating sequences. Our proposed methodology will contribute to various fields using “difficult sequence” peptides, such as pharmaceutical and materials science, as well as research for the diagnosis and treatment of protein/peptide misfolding diseases.

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Naushad, Mehjabeen, Siva Sundara Kumar Durairajan, Amal Kanti Bera, Sanjib Senapati, and Min Li. "Natural Compounds with Anti-BACE1 Activity as Promising Therapeutic Drugs for Treating Alzheimerʼs Disease." Planta Medica 85, no. 17 (October 16, 2019): 1316–25. http://dx.doi.org/10.1055/a-1019-9819.

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AbstractAlzheimerʼs disease is a neurodegenerative disease that leads to irreversible neuronal damage. Senile plaques, composed of amyloid beta peptide, is the principal abnormal characteristic of the disease. Among the factors involved, the secretase enzymes, namely, α secretase, beta-site amyloid precursor protein-cleaving enzyme, β secretase, and γ secretase, hold consequential importance. Beta-site amyloid precursor protein-cleaving enzyme 1 is considered to be the rate-limiting factor in the production of amyloid beta peptide. Research supporting the concept of inhibition of beta-site amyloid precursor protein-cleaving enzyme activity as one of the effective therapeutic targets in the mitigation of Alzheimerʼs disease is well accepted. The identification of natural compounds, such as β-amyloid precursor protein-selective beta-site amyloid precursor protein-cleaving enzyme inhibitors, and the idea of compartmentalisation of the beta-site amyloid precursor protein-cleaving enzyme 1 action have caused a dire need to closely examine the natural compounds and their effectiveness in the disease mitigation. Many natural compounds have been reported to effectively modulate beta-site amyloid precursor protein-cleaving enzyme 1. At lower doses, compounds like 2,2′,4′-trihydroxychalcone acid, quercetin, and myricetin have been shown to effectively reduce beta-site amyloid precursor protein-cleaving enzyme 1 activity. The currently used five drugs that are marketed and used for the management of Alzheimerʼs disease have an increased risk of toxicity and restricted therapeutic efficiency, hence, the search for new anti-Alzheimerʼs disease drugs is of primary concern. A variety of natural compounds having pure pharmacological moieties showing multitargeting activity and others exhibiting specific beta-site amyloid precursor protein-cleaving enzyme 1 inhibition as discussed below have superior biosafety. Many of these compounds, which are isolated from medicinal herbs and marine flora, have been long used for the treatment of various ailments since ancient times in the Chinese and Ayurvedic medical systems. The aim of this article is to review the available data on the selected natural compounds, giving emphasis to the inhibition of beta-site amyloid precursor protein-cleaving enzyme 1 activity as a mode of Alzheimerʼs disease treatment.

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Borutaite, Vilmante, Ramune Morkuniene, and Gintaras Valincius. "Beta-amyloid oligomers: recent developments." BioMolecular Concepts 2, no. 3 (June 1, 2011): 211–22. http://dx.doi.org/10.1515/bmc.2011.019.

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AbstractRecent studies point to a critical role of soluble β-amyloid oligomers in the pathogenesis of one of the most common neurodegenerative diseases, Alzheimer's disease (AD). Beta-amyloid peptides are cleavage products of a ubiquitously expressed protein, the amyloid precursor protein. Early studies suggested that accumulation of extracellular β-amyloid aggregates are the most toxic species causing synaptic dysfunction and neuronal loss in particular regions of the brain (neurobiological features underlying cognitive decline of the AD patients). In recent years, a shift of pardigm occurred, and now there is accumulating evidence that soluble oligomeric forms of the peptide are the most toxic to neuronal cells. In this review, we discuss recent findings on the toxic effects of amyloid-β oligomers, their physico-chemical properties and the possible pathways of their formation in vitro and in vivo.

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Ghiso, J., E. Matsubara, A. Koudinov, N. H. Choi-Miura, M. Tomita, T. Wisniewski, and B. Frangione. "The cerebrospinal-fluid soluble form of Alzheimer's amyloid β is complexed to SP-40,40 (apolipoprotein J), an inhibitor of the complement membrane-attack complex." Biochemical Journal 293, no. 1 (July 1, 1993): 27–30. http://dx.doi.org/10.1042/bj2930027.

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The amyloid fibrils deposited in Alzheimer's neuritic plaque cores and cerebral blood vessels are mainly composed of aggregated forms of a unique peptide, 39-42 amino acids long, named amyloid beta (A beta). A similar, although soluble, A beta (‘sA beta’) has been identified in cerebrospinal fluid, plasma and cell supernatants, indicating that it is normally produced by proteolytic processing of its precursor protein, amyloid precursor protein (APP). Using direct binding experiments we have isolated and characterized an 80 kDa circulating protein that specifically interacts with a synthetic peptide identical with A beta. The protein was unmistakably identified as SP-40,40 or ApoJ, a cytolytic inhibitor and lipid carrier, by means of amino acid sequence and immunoreactivity with specific antibodies. Immunoprecipitation with anti-SP-40,40 retrieved soluble A beta from cerebrospinal fluid, indicating that the interaction occurs in vivo.

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Matos, Jason O., Greg Goldblatt, and Suren A. Tatulian. "Pyroglutamylated Amyloid-Beta Peptide Reverses Cross Beta-Sheets by a Prion-Like Mechanism." Biophysical Journal 106, no. 2 (January 2014): 684a—685a. http://dx.doi.org/10.1016/j.bpj.2013.11.3788.

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Chiorcea-Paquim, Ana-Maria, Teodor Adrian Enache, and Ana Maria Oliveira-Brett. "Electrochemistry of Alzheimer Disease Amyloid Beta Peptides." Current Medicinal Chemistry 25, no. 33 (October 24, 2018): 4066–83. http://dx.doi.org/10.2174/0929867325666180214112536.

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Alzheimer’s disease (AD) is a widespread form of dementia that is estimated to affect 44.4 million people worldwide. AD pathology is closely related to the accumulation of amyloid beta (Aβ) peptides in fibrils and plagues, the small oligomeric intermediate species formed during the Aβ peptides aggregation presenting the highest neurotoxicity. This review discusses the recent advances on the Aβ peptides electrochemical characterization. The Aβ peptides oxidation at a glassy carbon electrode occurs in one or two steps, depending on the amino acid sequence, length and content. The first electron transfer reaction corresponds to the tyrosine Tyr10 amino acid residue oxidation, and the second to all three histidine (His6, His13 and His14) and one methionine (Met35) amino acid residues. The Aβ peptides aggregation and amyloid fibril formation are electrochemically detected via the electroactive amino acids oxidation peak currents decrease that occurs in a time dependent manner. The Aβ peptides redox behaviour is correlated with changes in the adsorption morphology from initially random coiled structures, corresponding to the Aβ peptide monomers in random coil or in α-helix conformations, to aggregates, protofibrils and two types of fibrils, corresponding to the Aβ peptides in a β-sheet configuration, observed by atomic force microscopy. Electrochemical studies of Aβ peptides aggregation, mediated by the interaction with metal ions, particularly zinc, copper and iron, and different methodologies concerning the detection of Aβ peptide biomarkers of AD in biological fluids, using electrochemical biosensors, are also discussed.

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Barden, C., F. Meier-Stephenson, MD Carter, S. Banfield, EC Diez, B. Kelly, E. Lu, et al. "Design and development of drugs for Alzheimer’s dementia as a protein misfolding disorder." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 42, S1 (May 2015): S16. http://dx.doi.org/10.1017/cjn.2015.95.

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Background: There are no disease modifying agents for the treatment of Alzheimer’s disease (AD). Pathologically, AD is associated with the misfolding of two peptides: beta-amyloid (plaques) and tau (tangles). Methods: Using large-scale computer simulations, we modelled the misfolding of both beta-amyloid and tau, identifying a common conformational motif (CCM; i.e. an abnormal peptide shape), present in both beta-amyloid and tau, that promotes their misfolding. We screened a library of 11.8 million compounds against this in silico model of protein misfolding, identifying three novel molecular classes of putative therapeutics as anti-protein misfolding agents. We synthesized approximately 400 new chemical entity drug-like molecules in each of these three classes (i.e. 1200 potential drug candidates). These were comprehensively screened in a battery of five in vitro protein oligomerization assays. Selected compounds were next evaluated in the APP/PS1 doubly transgenic mouse model of AD. Results: Two new classes of molecules were identified with the ability to block the oligomerization of both beta-amyloid and tau. These compounds are drug-like with good pharmacokinetic properties and are brain-penetrant. They exhibit excellent efficacy in transgenic mouse models. Conclusion: Computer aided drug design has enabled the discovery of novel drug-like molecules able to inhibit both tau and beta-amyloid misfolding.

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Gera, János, and Gábor Paragi. "Fluorescence-Labeled Amyloid Beta Monomer: A Molecular Dynamical Study." Molecules 25, no. 15 (August 1, 2020): 3524. http://dx.doi.org/10.3390/molecules25153524.

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The aggregation process of the Amyloidβ (Aβ) peptide is one of the central questions in Alzheimers’s research. Fluorescence-labeled single-molecule detection is a novel technique concerning the early stage investigation of Aβ aggregation, where the labeling dyes are covalently bound to the Aβ monomer. As the influence of the dye on the conformational space of the Aβ monomer can be significant, its effect on the seeding process is an open question. The applied fluorescent molecule continuously switches between an active (ON) and an inactive (OFF) state, where the latter supports an extra rotational restriction at many commercially available dyes. However, only a few theoretical studies simulated the Aβ monomer in the presence of a dye and none of them considered the difference between the ON and the OFF states. Therefore, we examined the impact of a selected fluorescence dye (Alexa 568) on the conformational space of the monomeric Aβ(1–42) peptide in its ON and OFF state by replica exchange molecular dynamic simulations. Investigations on secondary structure elements as well as dye-peptide contact analysis for the monomers are presented. Experimental and theoretical NMR shifts were contrasted to qualify the calculation protocol and theoretical values of the labeled and the non-labeled peptide were also compared. We found that the first five residues have higher helical propensity in the presence of the dye, and electrostatic properties could strongly affect the connection between the dye and the peptide parts.

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Airoldi, Cristina, Francisco Cardona, Erika Sironi, Laura Colombo, Mario Salmona, Ilaria Cambianica, Francesca Ornaghi, Giulio Sancini, Francesco Nicotra, and Barbara La Ferla. "Fluorescent amyloid β-peptide ligand derivatives as potential diagnostic tools for Alzheimer’s disease." Pure and Applied Chemistry 85, no. 9 (September 1, 2013): 1813–23. http://dx.doi.org/10.1351/pac-con-12-11-07.

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Aβ-peptide ligands based on a cis-glycofused benzopyran structure have been fluorescently labeled using coumarine derivatives. Among the synthesized compounds, two conserved their binding ability to β-amyloid peptides, as shown by NMR experiments. Moreover, exploiting its fluorescent property, it was demonstrated that one of such compounds was able to cross an in vitro model of blood–brain barrier (BBB) and to stain Aβ‑deposits.

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Ntarakas, Nikolaos, Inna Ermilova, and Alexander P. Lyubartsev. "Effect of lipid saturation on amyloid-beta peptide partitioning and aggregation in neuronal membranes: molecular dynamics simulations." European Biophysics Journal 48, no. 8 (October 26, 2019): 813–24. http://dx.doi.org/10.1007/s00249-019-01407-x.

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Abstract Aggregation of amyloid-$$\beta $$β (Aβ) peptides, cleaved from the amyloid precursor protein, is known as a precursor of the Alzheimer’s disease (AD). It is also known that Alzheimer’s disease is characterized by a substantial decrease of the amount of polyunsaturated lipids in the neuronal membranes of the frontal gray matter. To get insight into possible interconnection of these phenomena, we have carried out molecular dynamics simulations of two fragments of A$$\beta $$β peptide, A$$\beta $$β$$_{1-28}$$1-28 and A$$\beta $$β$$_{26-40}$$26-40, in four different lipid bilayers: two monocomponent ones (14:0-14:0 PC, 18:0-22:6 PC), and two bilayers containing mixtures of 18:0-18:0 PE, 22:6-22:6 PE, 16:0-16:0 PC and 18:1-18:1 PC lipids of composition mimicking neuronal membranes in a “healthy” and “AD” brain. The simulations showed that the presence of lipids with highly unsaturated 22:6cis fatty acids chains strongly affects the interaction of amyloid-$$\beta $$β peptides with lipid membranes. The polyunsaturated lipids cause stronger adsorption of A$$\beta $$β-peptides by the membrane and lead to weaker binding between peptides when the latter form aggregates. This difference in the behaviour observed in monocomponent bilayers is propagated in a similar fashion to the mixed membranes mimicking composition of neuronal membranes in “healthy” and “AD” brains, with “healthy” membrane having higher fraction of polyunsaturated lipids. Our simulations give strong indication that it can be physical–chemical background of the interconnection between amyloid fibrillization causing Alzheimer’s disease, and content of polyunsaturated lipids in the neuronal membranes.

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Mocanu, Cosmin Stefan, Marius Niculaua, Gheorghita Zbancioc, Violeta Mangalagiu, and Gabi Drochioiu. "Novel Design of Neuropeptide-Based Drugs with β-Sheet Breaking Potential in Amyloid-Beta Cascade: Molecular and Structural Deciphers." International Journal of Molecular Sciences 23, no. 5 (March 5, 2022): 2857. http://dx.doi.org/10.3390/ijms23052857.

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Our work discusses the investigation of 75 peptide-based drugs with the potential ability to break the β-sheet structures of amyloid-beta peptides from senile plaques. Hence, this study offers a unique insight into the design of neuropeptide-based drugs with β-sheet breaker potential in the amyloid-beta cascade for Alzheimer’s disease (AD). We started with five peptides (15QKLVFF20, 16KLVFF20, 17LVFF20, 16KLVF19 and 15QKLV18), to which 14 different organic acids were attached at the N-terminal. It was necessary to evaluate the physiochemical features of these sequences due to the biological correlation with our proposal. Hence, the preliminary analysis of different pharmacological features provided the necessary data to select the peptides with the best biocompatibility for administration purposes. Our approaches demonstrated that the peptides 17LVFF20, NA-17LVFF20, 16KLVF19 and NA-16KLVF19 (NA-nicotinic acid) have the ability to interfere with fibril formation and hence improve the neuro and cognitive functions. Moreover, the peptide conjugate NA-16KLVF19 possesses attractive pharmacological properties, demonstrated by in silico and in vitro studies. Tandem mass spectrometry showed no fragmentation for the spectra of 16KLVF19. Such important results suggest that under the action of protease, the peptide cleavage does not occur at all. Additionally, circular dichroism confirmed docking simulations and showed that NA-16KLVF19 may improve the β-sheet breaker mechanism, and thus the entanglement process of amyloid-beta peptides can be more effective.

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Candreva, Jason, Edward Chau, Edwin Aoraha, Vikas Nanda, and Jin Ryoun Kim. "Hetero-assembly of a dual β-amyloid variant peptide system." Chemical Communications 54, no. 49 (2018): 6380–83. http://dx.doi.org/10.1039/c8cc02724b.

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Festa, Giulia, Francesco Mallamace, Giulia Maria Sancesario, Carmelo Corsaro, Domenico Mallamace, Enza Fazio, Laura Arcidiacono, et al. "Aggregation States of Aβ1–40, Aβ1–42 and Aβp3–42 Amyloid Beta Peptides: A SANS Study." International Journal of Molecular Sciences 20, no. 17 (August 24, 2019): 4126. http://dx.doi.org/10.3390/ijms20174126.

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Aggregation states of amyloid beta peptides for amyloid beta A β 1 – 40 to A β 1 – 42 and A β p 3 – 42 are investigated through small angle neutron scattering (SANS). The knowledge of these small peptides and their aggregation state are of key importance for the comprehension of neurodegenerative diseases (e.g., Alzheimer’s disease). The SANS technique allows to study the size and fractal nature of the monomers, oligomers and fibrils of the three different peptides. Results show that all the investigated peptides have monomers with a radius of gyration of the order of 10 Å, while the oligomers and fibrils display differences in size and aggregation ability, with A β p 3 – 42 showing larger oligomers. These properties are strictly related to the toxicity of the corresponding amyloid peptide and indeed to the development of the associated disease.

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Haass, C., E. H. Koo, A. Capell, D. B. Teplow, and D. J. Selkoe. "Polarized sorting of beta-amyloid precursor protein and its proteolytic products in MDCK cells is regulated by two independent signals." Journal of Cell Biology 128, no. 4 (February 15, 1995): 537–47. http://dx.doi.org/10.1083/jcb.128.4.537.

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Progressive cerebral deposition of the amyloid (A beta) beta-protein is an early and invariant feature of Alzheimer's disease. A beta is derived by proteolysis from the membrane-spanning beta-amyloid precursor protein (beta APP). beta APP is processed into various secreted products, including soluble beta APP (APPs), the 4-kD A beta peptide, and a related 3-kD peptide (p3). We analyzed the mechanisms regulating the polarized basolateral sorting of beta APP and its proteolytic derivatives in MDCK cells. Deletion of the last 32 amino acids (residues 664-695) of the beta APP cytoplasmic tail had no influence on either the constitutive approximately 90% level of basolateral sorting of surface beta APP, or the strong basolateral secretion of APPs, A beta, and p3. However, deleting the last 42 amino acids (residues 654-695) or changing tyrosine 653 to alanine altered the distribution of cell surface beta APP so that approximately 40-50% of the molecules were inserted apically. In parallel, A beta was now secreted from both surfaces. Surprisingly, this change in surface beta APP had no influence on the basolateral secretion of APPs and p3. This result suggests that most beta APP molecules which give rise to APPs in MDCK cells are cleaved intracellularly before reaching the surface. Consistent with this conclusion, we readily detected intracellular APPs in carbonate extracts of isolated membrane vesicles. Moreover, ammonium chloride treatment resulted in the equal secretion of APPs into both compartments, as occurs with other non-membranous, basolaterally secreted proteins, but it did not influence the polarity of cell surface beta APP. These results demonstrate that in epithelial cells two independent mechanisms mediate the polarized trafficking of beta APP holoprotein and its major secreted derivative (APPs) and that A beta peptides are derived in part from beta APP holoprotein targeted to the cell surface by a signal that includes tyrosine 653.

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Kucheryavykh, Lilia Y., Jescelica Ortiz-Rivera, Yuriy V. Kucheryavykh, Astrid Zayas-Santiago, Amanda Diaz-Garcia, and Mikhail Y. Inyushin. "Accumulation of Innate Amyloid Beta Peptide in Glioblastoma Tumors." International Journal of Molecular Sciences 20, no. 10 (May 20, 2019): 2482. http://dx.doi.org/10.3390/ijms20102482.

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Immunostaining with specific antibodies has shown that innate amyloid beta (Aβ) is accumulated naturally in glioma tumors and nearby blood vessels in a mouse model of glioma. In immunofluorescence images, Aβ peptide coincides with glioma cells, and enzyme-linked immunosorbent assay (ELISA) have shown that Aβ peptide is enriched in the membrane protein fraction of tumor cells. ELISAs have also confirmed that the Aβ(1–40) peptide is enriched in glioma tumor areas relative to healthy brain areas. Thioflavin staining revealed that at least some amyloid is present in glioma tumors in aggregated forms. We may suggest that the presence of aggregated amyloid in glioma tumors together with the presence of Aβ immunofluorescence coinciding with glioma cells and the nearby vasculature imply that the source of Aβ peptides in glioma can be systemic Aβ from blood vessels, but this question remains unresolved and needs additional studies.

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Eckenhoff, Roderic G., Jonas S. Johansson, Huafeng Wei, Anna Carnini, Baobin Kang, Wenlin Wei, Ravindernath Pidikiti, Jason M. Keller, and Maryellen F. Eckenhoff. "Inhaled Anesthetic Enhancement of Amyloid-β Oligomerization and Cytotoxicity." Anesthesiology 101, no. 3 (September 1, 2004): 703–9. http://dx.doi.org/10.1097/00000542-200409000-00019.

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Background The majority of surgical patients receive inhaled anesthetics, principally small haloalkanes and haloethers. Long-term cognitive problems occur in the elderly subsequent to anesthesia and surgery, and previous surgery might also be a risk factor for neurodegenerative disorders like Alzheimer and Parkinson disease. The authors hypothesize that inhaled anesthetics contribute to these effects through a durable enhancement of peptide oligomerization. Methods Light scattering, filtration assays, electron microscopy, fluorescence spectroscopy and size-exclusion chromatography was used to characterize the concentration-dependent effects of halothane, isoflurane, propofol, and ethanol on amyloid beta peptide oligomerization. Pheochromocytoma cells were used to characterize cytotoxicity of amyloid oligomers with and without the above anesthetics. Results Halothane and isoflurane enhanced amyloid beta oligomerization rates and pheochromocytoma cytotoxicity in vitro through a preference for binding small oligomeric species. Ethanol and propofol inhibited oligomerization at low concentration but enhanced modestly at very high concentration. Neither ethanol nor propofol enhanced amyloid beta toxicity in pheochromocytoma cells. Conclusions Inhaled anesthetics enhance oligomerization and cytotoxicity of Alzheimer disease-associated peptides. In addition to the possibility of a general mechanism for anesthetic neurotoxicity, these results call for further evaluation of the interaction between neurodegenerative disorders, dementia, and inhalational anesthesia.

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Makino, Mitsuhiro, Kaori Ito-Takahashi, Akira Yano, Yoshikatsu Miwa, Yoshito Kanazawa, Akiko Chiba, Akira Kanda, and Shinji Murata. "P2-395: Effect of a novel beta-amyloid peptide vaccine on brain beta-amyloid deposition in Tg2576 mice." Alzheimer's & Dementia 9 (July 2013): P502—P503. http://dx.doi.org/10.1016/j.jalz.2013.05.1044.

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Wirths, Oliver, Gerd Multhaup, and Thomas A. Bayer. "A modified beta-amyloid hypothesis: intraneuronal accumulation of the beta-amyloid peptide - the first step of a fatal cascade." Journal of Neurochemistry 91, no. 3 (November 2004): 513–20. http://dx.doi.org/10.1111/j.1471-4159.2004.02737.x.

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Doytchinova, Irini, Mariyana Atanasova, Evdokiya Salamanova, Stefan Ivanov, and Ivan Dimitrov. "Curcumin Inhibits the Primary Nucleation of Amyloid-Beta Peptide: A Molecular Dynamics Study." Biomolecules 10, no. 9 (September 15, 2020): 1323. http://dx.doi.org/10.3390/biom10091323.

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The amyloid plaques are a key hallmark of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Amyloidogenesis is a complex long-lasting multiphase process starting with the formation of nuclei of amyloid peptides: a process assigned as a primary nucleation. Curcumin (CU) is a well-known inhibitor of the aggregation of amyloid-beta (Aβ) peptides. Even more, CU is able to disintegrate preformed Aβ firbils and amyloid plaques. Here, we simulate by molecular dynamics the primary nucleation process of 12 Aβ peptides and investigate the effects of CU on the process. We found that CU molecules intercalate among the Aβ chains and bind tightly to them by hydrogen bonds, hydrophobic, π–π, and cation–π interactions. In the presence of CU, the Aβ peptides form a primary nucleus of a bigger size. The peptide chains in the nucleus become less flexible and more disordered, and the number of non-native contacts and hydrogen bonds between them decreases. For comparison, the effects of the weaker Aβ inhibitor ferulic acid (FA) on the primary nucleation are also examined. Our study is in good agreement with the observation that taken regularly, CU is able to prevent or at least delay the onset of neurodegenerative disorders.

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Ştefănescu, Raluca, Gabriela Dumitriṭa Stanciu, Andrei Luca, Ioana Cezara Caba, Bogdan Ionel Tamba, and Cosmin Teodor Mihai. "Contributions of Mass Spectrometry to the Identification of Low Molecular Weight Molecules Able to Reduce the Toxicity of Amyloid-β Peptide to Cell Cultures and Transgenic Mouse Models of Alzheimer’s Disease." Molecules 24, no. 6 (March 24, 2019): 1167. http://dx.doi.org/10.3390/molecules24061167.

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Alzheimer’s Disease affects approximately 33 million people worldwide and is characterized by progressive loss of memory at the cognitive level. The formation of toxic amyloid oligomers, extracellular amyloid plaques and amyloid angiopathy in brain by amyloid beta peptides are considered a part of the identified mechanism involved in disease pathogenesis. The optimal treatment approach leads toward finding a chemical compound able to form a noncovalent complex with the amyloid peptide thus blocking the process of amyloid aggregation. This direction gained an increasing interest lately, many studies demonstrating that mass spectrometry is a valuable method useful for the identification and characterization of such molecules able to interact with amyloid peptides. In the present review we aim to identify in the scientific literature low molecular weight chemical compounds for which there is mass spectrometric evidence of noncovalent complex formation with amyloid peptides and also there are toxicity reduction results which verify the effects of these compounds on amyloid beta toxicity towards cell cultures and transgenic mouse models developing Alzheimer’s Disease.

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JALILI, S., and M. AKHAVAN. "A MOLECULAR DYNAMICS SIMULATION STUDY OF CONFORMATIONAL CHANGES AND SOLVATION OF Aβ PEPTIDE IN TRIFLUOROETHANOL AND WATER." Journal of Theoretical and Computational Chemistry 08, no. 02 (April 2009): 215–31. http://dx.doi.org/10.1142/s0219633609004769.

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Molecular dynamics (MD) simulations of amyloid beta peptide have been performed in aqueous solutions of trifluoroethanol with different concentrations. The amount of α-helical secondary structure increases when going from pure water to trifluoroethanol-rich solutions. The conformation obtained in 40% (v/v) trifluoroethanol solution is very similar to the experimental observations of beta peptide in sodium dodecyl sulfate micelle. In this solution, the peptide has two helical segments connected through a looped region. The C-terminal helix of beta peptide unfolds in pure water. The effect of trifluoroethanol on peptide's secondary structure has been explained using the properties calculated from MD trajectories.

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Gomes, Luiza M. F., Atif Mahammed, Kathleen E. Prosser, Jason R. Smith, Michael A. Silverman, Charles J. Walsby, Zeev Gross, and Tim Storr. "A catalytic antioxidant for limiting amyloid-beta peptide aggregation and reactive oxygen species generation." Chemical Science 10, no. 6 (2019): 1634–43. http://dx.doi.org/10.1039/c8sc04660c.

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Lange, Johannes, Kristin Aaser Lunde, Camilla Sletten, Simon Geir Møller, Ole-Bjørn Tysnes, Guido Alves, Jan Petter Larsen, and Jodi Maple-Grødem. "Association of aBACE1Gene Polymorphism with Parkinson’s Disease in a Norwegian Population." Parkinson's Disease 2015 (2015): 1–5. http://dx.doi.org/10.1155/2015/973298.

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Background. Parkinson’s disease (PD) and Alzheimer’s disease (AD) share pathological features, including amyloid-beta pathology. Amyloid-beta peptide is generated by sequential proteolysis of amyloid precursor protein (APP), and genetic variations in the processing pathway genes have been found to increase the risk of AD; however, the contribution in PD is unknown.Methods. The aim of this study was to investigate whether candidate polymorphisms in five genes (ADAM10,BACE1,BACE2,PSEN2, andCLU) involved in the APP processing pathway affect PD risk in a population-based cohort of patients with incident PD and control subjects from the Norwegian ParkWest study.Results. We found an association of rs638405 inBACE1with increased risk of PD, thus providing a novel link, at the genetic level, between amyloid-beta pathology and PD.

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Paulsson, Johan F., Sebastian W. Schultz, Martin Köhler, Ingo Leibiger, Per-Olof Berggren, and Gunilla T. Westermark. "Real-Time Monitoring of Apoptosis by Caspase-3-Like Protease Induced FRET Reduction Triggered by Amyloid Aggregation." Experimental Diabetes Research 2008 (2008): 1–12. http://dx.doi.org/10.1155/2008/865850.

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Amyloid formation is cytotoxic and can activate the caspase cascade. Here, we monitor caspase-3-like activity as reduction of fluorescence resonance energy transfer (FRET) using the contstruct pFRET2-DEVD containing enhanced cyan fluorescent protin (EYFP) linked by the caspase-3 specific cleavage site residues DEVD. Beta-TC-6 cells were transfected, and the fluoorescence was measured at 440 nm excitation and 535 nm (EYFP) and 480 nm (ECFP) emission wavelength. Cells were incubated with recombinant pro lset Amyloid Polypeptide (recprolAPP) or the processing metabolites of prolAPP; the N-terminal flanking peptide withIAPP (recN+IAPP); IAPP with the C-terminal flanking peptied (recIAPP+C) and lslet Amyloid Polypeptide (recIAPP) . Peptides were added in solubilized from (50 μM) or as performed amyloid-like fibrils, or as a combination of these. FRET was measured and incubation with a mixture of solubilized peptide and performed fibrils resulted in loss of FRET and apoptosis was determined to occure in cells incubated withrecproIAPP (49%),recN+IAPP (46%),recIAPP (72%) andrecIAPP+C (59%). These results show that proIAPP and the processing intermediates reside the same cell toxic capacity as IAPP, and they can all have a central role in the reduction of beta-cell number in type 2 diabetes.

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Ramaswamy, Keerthana, Priyadharshini Kumaraswamy, Swaminathan Sethuraman, and Uma Maheswari Krishnan. "Self-assembly characteristics of a structural analogue of Tjernberg peptide." RSC Adv. 4, no. 32 (2014): 16517–23. http://dx.doi.org/10.1039/c3ra47754a.

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This article aims to understand the pathogenesis behind the formation of amyloid plaques using a modified version of the KLVFF peptide. It was found that the cytotoxicity of the nanostructures formed by the RIVFF peptide may be attributed to the aminoacids with long side chains along with hydrophobic aminoacids resembling the amyloid beta peptide.

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Parkin, Edward T., Jessica E. Hammond, Lauren Owens, and Matthew D. Hodges. "The orphan drug dichloroacetate reduces amyloid beta-peptide production whilst promoting non-amyloidogenic proteolysis of the amyloid precursor protein." PLOS ONE 17, no. 1 (January 13, 2022): e0255715. http://dx.doi.org/10.1371/journal.pone.0255715.

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The amyloid cascade hypothesis proposes that excessive accumulation of amyloid beta-peptides is the initiating event in Alzheimer’s disease. These neurotoxic peptides are generated from the amyloid precursor protein via sequential cleavage by β- and γ-secretases in the ’amyloidogenic’ proteolytic pathway. Alternatively, the amyloid precursor protein can be processed via the ’non-amyloidogenic’ pathway which, through the action of the α-secretase a disintegrin and metalloproteinase (ADAM) 10, both precludes amyloid beta-peptide formation and has the additional benefit of generating a neuroprotective soluble amyloid precursor protein fragment, sAPPα. In the current study, we investigated whether the orphan drug, dichloroacetate, could alter amyloid precursor protein proteolysis. In SH-SY5Y neuroblastoma cells, dichloroacetate enhanced sAPPα generation whilst inhibiting β–secretase processing of endogenous amyloid precursor protein and the subsequent generation of amyloid beta-peptides. Over-expression of the amyloid precursor protein partly ablated the effect of dichloroacetate on amyloidogenic and non-amyloidogenic processing whilst over-expression of the β-secretase only ablated the effect on amyloidogenic processing. Similar enhancement of ADAM-mediated amyloid precursor protein processing by dichloroacetate was observed in unrelated cell lines and the effect was not exclusive to the amyloid precursor protein as an ADAM substrate, as indicated by dichloroacetate-enhanced proteolysis of the Notch ligand, Jagged1. Despite altering proteolysis of the amyloid precursor protein, dichloroacetate did not significantly affect the expression/activity of α-, β- or γ-secretases. In conclusion, dichloroacetate can inhibit amyloidogenic and promote non-amyloidogenic proteolysis of the amyloid precursor protein. Given the small size and blood-brain-barrier permeability of the drug, further research into its mechanism of action with respect to APP proteolysis may lead to the development of therapies for slowing the progression of Alzheimer’s disease.

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TAKENOUCHI, Takahito, and Eisuke MUNEKATA. "Amyloid .BETA.-Peptide. A Putative Key Substance of Alzheimer's Disease." Kagaku To Seibutsu 33, no. 12 (1995): 776–83. http://dx.doi.org/10.1271/kagakutoseibutsu1962.33.776.

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Hu, Yang, Baihao Su, HeQiu Zheng, and Jin Ryoun Kim. "A peptide probe for detection of various beta-amyloid oligomers." Molecular BioSystems 8, no. 10 (2012): 2741. http://dx.doi.org/10.1039/c2mb25148e.

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Mattson, M. P. "Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives." Physiological Reviews 77, no. 4 (October 1, 1997): 1081–132. http://dx.doi.org/10.1152/physrev.1997.77.4.1081.

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beta-Amyloid precursor protein (beta-APP), the source of the fibrillogenic amyloid beta-peptide (A beta) that accumulates in the brain of victims of Alzheimer's disease, is a multifunctional protein that is widely expressed in the nervous system. beta-Amyloid precursor protein is axonally transported and accumulates in presynaptic terminals and growth cones. A secreted form of beta-APP (sAPP alpha) is released from neurons in response to electrical activity and may function in modulation of neuronal excitability, synaptic plasticity, neurite outgrowth, synaptogenesis, and cell survival. A signaling pathway involving guanosine 3',5'-cyclic monophosphate is activated by sAPP alpha and modulates the activities of potassium channels, N-methyl-D-aspartate receptors, and the transcription factor NF kappa B. Additional functions of beta-APP may include modulation of cell adhesion and regulation of proliferation of nonneuronal cells. Alternative enzymatic processing of beta-APP liberates A beta, which has a propensity to form amyloid fibrils; A beta can damage and kill neurons and increase their vulnerability to excitotoxicity. The mechanism involves generation of oxyradicals and impairment of membrane transport systems (e.g., ion-motive ATPases and glutamate and glucose transporters). Genetic mutations or age-related metabolic changes may promote neuronal degeneration in Alzheimer's disease by increasing production of A beta and/or decreasing levels of neuroprotective sAPP alpha.

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Lee, Joo-Hee, Na-Hyun Ahn, Su-Bin Choi, Youngeun Kwon, and Seung-Hoon Yang. "Natural Products Targeting Amyloid Beta in Alzheimer’s Disease." International Journal of Molecular Sciences 22, no. 5 (February 26, 2021): 2341. http://dx.doi.org/10.3390/ijms22052341.

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Alzheimer’s disease (AD) is a neurodegenerative disease characterized by severe brain damage and dementia. There are currently few therapeutics to treat this disease, and they can only temporarily alleviate some of the symptoms. The pathogenesis of AD is mainly preceded by accumulation of abnormal amyloid beta (Aβ) aggregates, which are toxic to neurons. Therefore, modulation of the formation of these abnormal aggregates is strongly suggested as the most effective approach to treat AD. In particular, numerous studies on natural products associated with AD, aiming to downregulate Aβ peptides and suppress the formation of abnormal Aβ aggregates, thus reducing neural cell death, are being conducted. Generation of Aβ peptides can be prevented by targeting the secretases involved in Aβ-peptide formation (secretase-dependent). Additionally, blocking the intra- and intermolecular interactions of Aβ peptides can induce conformational changes in abnormal Aβ aggregates, whereby the toxicity can be ameliorated (structure-dependent). In this review, AD-associated natural products which can reduce the accumulation of Aβ peptides via secretase- or structure-dependent pathways, and the current clinical trial states of these products are discussed.

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Strosznajder, J. B., H. Jeśko, and R. P. Strosznajder. "Effect of amyloid beta peptide on poly(ADP-ribose) polymerase activity in adult and aged rat hippocampus." Acta Biochimica Polonica 47, no. 3 (September 30, 2000): 847–54. http://dx.doi.org/10.18388/abp.2000_4003.

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It is suggested that the fibrillar amyloid beta peptide (A beta) in brain plays a direct role in neurodegeneration in Alzheimer's disease, probably through activation of reactive oxygen species formation. Free radicals and numerous neurotoxins elicit DNA damage that subsequently activates poly(ADP-ribose) polymerase (PARP, EC 2.4.2.30). In this study the effect of neurotoxic fragment (25-35) of full length A beta peptide on PARP activity in adult and aged rat hippocampus was investigated. In adult (4 month old) rat hippocampus the A beta 25-35 peptide significantly enhanced PARP activity by about 80% but had no effect on PARP activity in cerebral cortex and in hippocampus from aged (24-27 month old) rats. The effect of A beta peptide was reduced by half by the nitric oxide synthase inhibitor N-nitro-L-arginine. Stimulation of glutamate receptor(s) itself enhanced PARP activity by about 80% in adult hippocampus. However, A beta 25-35 did not exert any additional stimulatory effect. These results indicate that A beta, through NO and probably other free radicals, induces activation of DNA bound PARP activity exclusively in adult but not in aged hippocampus.

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Ghiso, J., A. Rostagno, J. E. Gardella, L. Liem, P. D. Gorevic, and B. Frangione. "A 109-amino-acid C-terminal fragment of Alzheimer's-disease amyloid precursor protein contains a sequence, -RHDS-, that promotes cell adhesion." Biochemical Journal 288, no. 3 (December 15, 1992): 1053–59. http://dx.doi.org/10.1042/bj2881053.

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Amyloid beta (A beta), the major constituent of the fibrils composing senile plaques and vascular amyloid deposits in Alzheimer's disease (AD) and related disorders, is a 39-42-residue self-aggregating degradation peptide of a larger multidomain membrane glycoprotein designated amyloid precursor protein (APP). An array of biological functions has been assigned to different APP domains, including growth regulation, neurotoxicity, inhibitory activity of serine proteinases and promotion of cell-cell and cell-matrix interactions. A beta is generated through an as-yet-unknown catabolic pathway that by-passes or inhibits the cleavage of APP within the A beta sequence. We have identified a 16 kDa intermediate APP C-terminal fragment containing A beta in leptomeningeal vessels of aged normal individuals and AD patients by means of its immunoreactivity with a panel of four different anti-(APP C-terminal) antibodies, indicating a different pathway of APP processing. Previous studies have indicated that the APP C-terminal domain is the most likely to be involved in cell-matrix interactions. A 109-amino-acid construct C109 with a sequence analogous to the C-terminal of APP (positions 587-695 of APP695), similar in length and immunoreactivity to the 16 kDa fragment, was found to promote cell adhesion. By use of synthetic peptides, this activity was initially located to the extracellular 28 residues of A beta. Inhibition studies demonstrated that the sequence RHDS (amino acids 5-8 of A beta, corresponding to residues 601-604 of APP695 was responsible for the adhesion-promoting activity. The interaction is dependent on bivalent cations and can be blocked either by the tetrapeptides RHDS and RGDS or by an anti-(beta 1 integrin) antibody. Thus, through integrin-like surface receptors, APP or its derivative proteolytic fragments containing the sequence RHDS may modulate cell-cell or cell-matrix interactions.

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Owens, Lauren, Joshua Bracewell, Alexandre Benedetto, Neil Dawson, Christopher Gaffney, and Edward Parkin. "BACE1 Overexpression Reduces SH-SY5Y Cell Viability Through a Mechanism Distinct from Amyloid-β Peptide Accumulation: Beta Prime-Mediated Competitive Depletion of sAβPPα." Journal of Alzheimer's Disease 86, no. 3 (April 5, 2022): 1201–20. http://dx.doi.org/10.3233/jad-215457.

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Background: The Alzheimer’s disease (AD)-associated amyloid-beta protein precursor (AβPP) can be cleaved by β-site AβPP cleaving enzyme 1 (BACE1) and the γ-secretase complex to yield neurotoxic amyloid-β (Aβ) peptides. However, AβPP can also be cleaved in a ‘non-amyloidogenic’ manner either by α-secretase to produce soluble AβPP alpha (sAβPPα) (a fragment with neuroprotective/neurogenic functions) or through alternative BACE1-mediated ‘beta prime’ activity yielding soluble AβPP beta prime (sAβPPβ’). Objective: To determine whether sAβPPα depletion, as opposed to Aβ peptide accumulation, contributes to cytotoxicity in AD-relevant SH-SY5Y neuroblastoma cell models. Methods: AβPP proteolysis was characterized by immunoblotting in mock-, wild-type AβPP (wtAβPP)-, BACE1-, and Swedish mutant AβPP (SweAβPP)-transfected cells. AβPP beta prime cleavage was confirmed through secretase inhibitor studies and C-terminal fragment analysis. The roles of sAβPPα and sAβPPβ’ in cell viability were confirmed by overexpression studies. Results: Despite producing enhanced Aβ peptide levels, wtAβPP- and SweAβPP-transfected cells did not exhibit reduced viability whereas BACE1-transfected cells did. sAβPPα generation in SH-SY5Y-BACE1 cells was virtually ablated in lieu of BACE1-mediated sAβPPβ’ production. sAβPPα overexpression in SH-SY5Y-BACE1 cells restored viability whereas sAβPPβ’ overexpression decreased viability further. The anti-AβPP 6E10 antibody was shown to cross-react with sAβPPβ’. Conclusion: sAβPPα depletion and/or sAβPPβ’ accumulation, but not elevated Aβ peptide levels, represent the cytotoxic mechanism following BACE1 overexpression in SH-SY5Y cells. These data support the novel concept that competitive sAβPPα depletion by BACE1 beta prime activity might contribute to AD. The cross-reactivity of 6E10 with AβPPβ’also questions whether previous studies assessing sAβPPα as a biomarker using this antibody should be revisited.

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Amtul, Zareen, Markus Uhrig, Rosanna Supino, and Konrad Beyreuther. "Phospholipids and a phospholipid-rich diet alter the in vitro amyloid-beta peptide levels and amyloid-beta 42/40 ratios." Neuroscience Letters 481, no. 2 (September 2010): 73–77. http://dx.doi.org/10.1016/j.neulet.2010.06.046.

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Jiang, Xing, Abigail J. Halmes, Giuseppe Licari, John W. Smith, Yang Song, Edwin G. Moore, Qian Chen, Emad Tajkhorshid, Chad M. Rienstra, and Jeffrey S. Moore. "Multivalent Polymer–Peptide Conjugates: A General Platform for Inhibiting Amyloid Beta Peptide Aggregation." ACS Macro Letters 8, no. 10 (September 30, 2019): 1365–71. http://dx.doi.org/10.1021/acsmacrolett.9b00559.

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Zaretsky, Dmitry V., Maria V. Zaretskaia, and Yaroslav I. Molkov. "Patients with Alzheimer’s disease have an increased removal rate of soluble beta-amyloid-42." PLOS ONE 17, no. 10 (October 31, 2022): e0276933. http://dx.doi.org/10.1371/journal.pone.0276933.

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Senile plaques, which are mostly composed of beta-amyloid peptide, are the main signature of Alzheimer’s disease (AD). Two main forms of beta-amyloid in humans are 40 and 42-amino acid, long; the latter is considered more relevant to AD etiology. The concentration of soluble beta-amyloid-42 (Aβ42) in cerebrospinal fluid (CSF-Aβ42) and the density of amyloid depositions have a strong negative correlation. However, AD patients have lower CSF-Aβ42 levels compared to individuals with normal cognition (NC), even after accounting for this correlation. The goal of this study was to infer deviations of Aβ42 metabolism parameters that underlie this difference using data from the Alzheimer’s Disease Neuroimaging Initiative cohort. Aβ42 is released to the interstitial fluid (ISF) by cells and is removed by several processes. First, growth of insoluble fibrils by aggregation decreases the concentration of soluble beta-amyloid in the ISF. Second, Aβ42 is physically transferred from the brain to the CSF and removed with the CSF flow. Finally, there is an intratissue removal of Aβ42 ending in proteolysis, which can occur either in the ISF or inside the cells after the peptide is endocytosed. Unlike aggregation, which preserves the peptide in the brain, transfer to the CSF and intratissue proteolysis together represent amyloid removal. Using a kinetic model of Aβ42 turnover, we found that compared to NC subjects, AD patients had dramatically increased rates of amyloid removal. A group with late-onset mild cognitive impairment (LMCI) also exhibited a higher rate of amyloid removal; however, this was less pronounced than in the AD group. Estimated parameters in the early-onset MCI group did not differ significantly from those in the NC group. We hypothesize that increased amyloid removal is mediated by Aβ42 cellular uptake; this is because CSF flow is not increased in AD patients, while most proteases are intracellular. Aβ cytotoxicity depends on both the amount of beta-amyloid internalized by cells and its intracellular conversion into toxic products. We speculate that AD and LMCI are associated with increased cellular amyloid uptake, which leads to faster disease progression. The early-onset MCI (EMCI) patients do not differ from the NC participants in terms of cellular amyloid uptake. Therefore, EMCI may be mediated by the increased production of toxic amyloid metabolites.

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Yagui, Kazuo, Takahide Yamaguchi, Azuma Kanatsuka, Fumio Shimada, Choug I. Huang, Yoshiharu Tokuyama, Haruhiko Ohsawa, et al. "Formation of islet amyloid fibrils in beta-secretory granules of transgenic mice expressing human islet amyloid polypeptide/amylin." European Journal of Endocrinology 132, no. 4 (April 1995): 487–96. http://dx.doi.org/10.1530/eje.0.1320487.

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Yagui K, Yamaguchi T, Kanatsuka A, Shimada F, Huang CI, Tokuyama Y, Ohsawa H, Yamamura K, Miyazaki J. Mikata A, Yoshida S, Makino H. Formation of islet amyloid fibrils in beta-secretory granules of transgenic mice expressing human islet amyloid polypeptide/amylin. Eur J Endocrinol 1995:132:487–96. ISSN 0804–4643 To investigate the relationship between human islet amyloid polypeptide (IAPP)/amylin expression and islet amyloid deposits in the pathogenesis of human non-insulin-dependent diabetes mellitus (NIDDM), we developed transgenic mice using a human IAPP cDNA connected to an insulin promoter. Ribonucleic acid blotting and immunohistochemistry revealed the expression of the transgene in the pancreatic beta cells. Immunogold electron microscopy showed that beta-secretory granules contained the human C-terminal flanking peptide of the IAPP precursor. Reverse-phase HPLC demonstrated human and mouse IAPP amide in the pancreas. Electron microscopy showed the accumulation of fibril-like material in a considerable number of beta-secretory granules. These results suggest that in transgenic mice, the human IAPP precursor is expressed in beta cells and becomes normally sorted into beta-secretory granules in which normal conversion to mature human IAPP takes place. The human IAPP molecules, because of their amyloidogenesis, aggregate into amyloid fibrils in secretory granules. Glucose tolerance was normal at 7 months old and islet amyloid was not observed. A longer time may be required for islet amyloid deposits and hyperglycemia to develop in mice. Our working hypothesis is that in human NIDDM, IAPP aggregates into amyloid fibrils in beta-secretory granules, and that the fibrils are released into the extracellular space and islet amyloid deposits become substantial with time. Azuma Kanatsuka, Second Department of Internal Medicine, Chiba University School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260, Japan

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Hernández, Félix, Elena Gómez de Barreda, Almudena Fuster-Matanzo, José J. Lucas, and Jesús Avila. "GSK3: A possible link between beta amyloid peptide and tau protein." Experimental Neurology 223, no. 2 (June 2010): 322–25. http://dx.doi.org/10.1016/j.expneurol.2009.09.011.

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Vassilakopoulou, Vyronia, Chrysoula-Evangelia Karachaliou, Alexandra Evangelou, Christos Zikos, and Evangelia Livaniou. "Peptide-Based Vaccines for Neurodegenerative Diseases: Recent Endeavors and Future Perspectives." Vaccines 9, no. 11 (November 4, 2021): 1278. http://dx.doi.org/10.3390/vaccines9111278.

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The development of peptide-based vaccines for treating human neurodegenerative diseases has been the eventual aim of many research endeavors, although no active immunotherapies have been approved for clinical use till now. A typical example of such endeavors is the effort to develop vaccines for Alzheimer’s disease based on the beta-amyloid peptide, which continues to be intensively investigated despite previous setbacks. In this paper, recent developments in peptide-based vaccines which target beta-amyloid as well as tau protein and α-synuclein are presented. Particular focus has been directed toward peptide epitopes and formulation systems selected/developed and employed to enhance vaccine efficacy and safety. Results from both, human clinical trials and animal preclinical studies conducted mainly in transgenic mice have been included. Future perspectives on the topic are also briefly discussed.

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Kim, Min Jeong, Ji-Hyun Kim, Ji Hyun Kim, Sanghyun Lee, and Eun Ju Cho. "Amelioration effects of Cirsium japonicum var. maackii extract/fractions on amyloid beta25–35-induced neurotoxicity in SH-SY5Y cells and identification of the main bioactive compound." Food & Function 11, no. 11 (2020): 9651–61. http://dx.doi.org/10.1039/d0fo01041c.

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Lichti, Cheryl, Anthony N. Vomund, Orion J. Peterson, Xiaoxiao Wan, and Emil R. Unanue. "Analysis of the nonobese diabetic mouse islet MHC-II peptidome reveals posttranslationally modified autoantigens." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 142.12. http://dx.doi.org/10.4049/jimmunol.204.supp.142.12.

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Abstract Autoimmune diabetes results from the destruction of insulin-producing beta cells, a process initiated by CD4 T cells recognizing MHC-II bound beta cell-derived peptides. We identified MHC-II bound peptides in the islets and throughout the peripheral lymphatic system in order to better understand diabetes initiation and progression. Toward this end, we performed unbiased nanoflow liquid chromatography-tandem mass spectrometry (nLC-MS/MS) analysis to obtain sequence information for MHC-II peptides isolated from islets, pancreatic lymph nodes and spleens of nonobese diabetic (NOD) mice. Peptides derived from beta cell proteins were further examined for their relative I-Ag7 binding strength and CD4 T cell autoreactivity. For a discussion of the major immunogenic peptides derived from the B chain of insulin and from C peptide, see the abstract of Wan et al. Herein we discuss the finding of a deamidated C peptide fragment and our search for fused peptides. We identified the deamidated insulin-1 C peptide fragment Ins1C:51–61, LQTLALEVARE. Evidence in the literature supports this C-terminal deamidation as being spontaneous rather than enzyme-mediated. Deamidation improved I-Ag7 binding compared to the wild type peptide and increased its immunogenicity, demonstrating the biological importance of this modification. The homologous peptide from insulin-2 was not identified, indicating a possible sequence bias for spontaneous deamidation. We identified only one fused peptide bound to I-Ag7, an insulin C peptide-islet amyloid polypeptide hybrid insulin peptide (HIP) that matches the previously reported HIP6.9. We also identified several free fused peptides in crinosomes and posit this as the probable site of their formation.

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Gault, Victor A., and Christian Hölscher. "Protease-Resistant Glucose-Dependent Insulinotropic Polypeptide Agonists Facilitate Hippocampal LTP and Reverse the Impairment of LTP Induced by Beta-Amyloid." Journal of Neurophysiology 99, no. 4 (April 2008): 1590–95. http://dx.doi.org/10.1152/jn.01161.2007.

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Type 2 diabetes has been identified as a risk factor for Alzheimer's disease (AD). Insulin signaling is often impaired in AD, contributing to the neurodegeneration observed in AD patients. One potential strategy to overcome this impairment is to normalize insulin signaling in the brain. In the present study, we have examined the effects of an enzyme-resistant analogue of glucose-dependent insulinotropic polypeptide (GIP), N-AcGIP, on synaptic plasticity. N-AcGIP is a stable, long-acting peptide hormone that regulates glucose homeostasis and insulin release. We tested the effects of native GIP and the agonist N-AcGIP on synaptic plasticity [long-term potentiation (LTP)] in the hippocampus [15 nmol, administered intracerebroventricularly (icv)] and report for the first time that both peptides have enhancing effects on LTP. In contrast, the antagonist of GIP, Pro(3)GIP (15 nmol icv), reduced LTP. Injection of beta-amyloid(25–35) (100 nmol), a peptide that aggregates in brains of AD patients, also impaired LTP. The injection of N-AcGIP (15 nmol icv) 30 min prior to injection of amyloid(25–35) (100 nmol icv) fully reversed the impairment of LTP induced by beta-amyloid. The results demonstrate for the first time that GIP (particularly enzyme-resistant forms) not only directly modulates neurotransmitter release and LTP formation, but also protects synapses from the detrimental effects of beta-amyloid fragments on LTP formation. The use of enzyme-resistant analogues of GIP show great promise as a potential novel treatment for preventing neurodegenerative processes in AD and other related disorders.

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Liu, Sijun, Yuying Zhao, Xiaoying Su, Chengcheng Zhou, Peifen Yang, Qiusan Lin, Shijun Li, et al. "Reconstruction of Alzheimer’s Disease Cell Model In Vitro via Extracted Peripheral Blood Molecular Cells from a Sporadic Patient." Stem Cells International 2020 (December 18, 2020): 1–10. http://dx.doi.org/10.1155/2020/8897494.

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The establishment of human-induced pluripotent stem cell (iPSC) models from sporadic Alzheimer’s disease (sAD) patients is necessary and could potentially benefit research into disease etiology and therapeutic strategies. However, the development of sAD iPSC models is still limited due to the multifactorial nature of the disease. Here, we extracted peripheral blood mononuclear cells (PBMCs) from a patient with sAD and induced them into iPSC by introducing the Sendai virus expressing Oct3/4, Sox2, c-Myc, and Klf4, which were subsequently induced into neural cells to build the cell model of AD. Using alkaline phosphatase staining, immunofluorescence staining, karyotype analysis, reverse transcription-polymerase chain reaction (RT-PCR), and teratoma formation in vitro, we demonstrated that the iPSC derived from PMBCs (PBMC-iPSC) had a normal karyotype and potential to differentiate into three embryonic layers. Immunofluorescence staining and quantitative real-time polymerase chain reaction (qPCR) suggested that PBMC-iPSCs were successfully differentiated into neural cells. Detection of beta-amyloid protein oligomer (AβO), beta-amyloid protein 1-40 (Aβ 1-40), and beta-amyloid protein 1-42 (Aβ 1-42) indicated that the AD cell model was satisfactorily constructed in vitro. In conclusion, this study has successfully generated an AD cell model with pathological features of beta-amyloid peptide deposition using PBMC from a patient with sAD.

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Atanasova, Mariana, Ivan Dimitrov, and Stefan Ivanov. "Molecular Dynamics Simulations of Acetylcholinesterase – Beta-Amyloid Peptide Complex." Cybernetics and Information Technologies 20, no. 6 (December 1, 2020): 140–54. http://dx.doi.org/10.2478/cait-2020-0068.

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Abstract Alzheimer’s Disease (AD) is a neurodegenerative disorder with severe consequences and lethal outcome. One of the pathological hallmarks of the disease is the formation of insoluble intercellular beta-Amyloid (Aβ) plaques. The enzyme ACetylcholinEsterase (AChE) promotes and accelerates the aggregation of toxic Aβ protofibrils progressively converted into plaques. The Peripheral Anionic Site (PAS), part of the binding gorge of AChE, is one of the nucleation centers implicated in the Aβ aggregation. In this study, the Aβ peptide was docked into the PAS and the stability of the formed complex was investigated by molecular dynamics simulation for 1 μs (1000 ns). The complex was stable during the simulation. Apart from PAS, the Aβ peptide makes several additional contacts with AChE. The main residence area of Aβ on the surface of AChE is the region 344-361. This region is next to PAS but far enough to be sterically hindered by dual-site binding AChE inhibitors.

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Journal articles on the topic 'Amyloid-beta peptide (A-beta)'

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