Oil Palm Phenolics Inhibit theIn VitroAggregation ofβ-Amyloid Peptide into Oligomeric Complexes

Alzheimer’s disease is a severe neurodegenerative disease characterized by the aggregation of amyloid-βpeptide (Aβ) into toxic oligomers which activate microglia and astrocytes causing acute neuroinflammation. Multiple studies show that the soluble oligomers of Aβ42 are neurotoxic and proinflammatory, whereas the monomers and insoluble fibrils are relatively nontoxic. We show that Aβ42 aggregation is inhibitedin vitroby oil palm phenolics (OPP), an aqueous extract from the oil palm tree(Elaeis guineensis). The data shows that OPP inhibits stacking ofβ-pleated sheets, which is essential for oligomerization. We demonstrate the inhibition of Aβ42 aggregation by (1) mass spectrometry; (2) Congo Red dye binding; (3) 2D-IR spectroscopy; (4) dynamic light scattering; (5) transmission electron microscopy; and (6) transgenic yeast rescue assay. In the yeast rescue assay, OPP significantly reduces the cytotoxicity of aggregating neuropeptides in yeast genetically engineered to overexpress these peptides. The data shows that OPP inhibits (1) the aggregation of Aβinto oligomers; (2) stacking ofβ-pleated sheets; and (3) fibrillar growth and coalescence. These inhibitory effects prevent the formation of neurotoxic oligomers and hold potential as a means to reduce neuroinflammation and neuronal death and thereby may play some role in the prevention or treatment of Alzheimer’s disease.

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Anti-Aggregation Property of Allicin by In Vitro and Molecular Docking Studies

Journal of Experimental Neuroscience ◽

10.1177/1179069519866185 ◽

2019 ◽

Vol 13 ◽

pp. 117906951986618 ◽

Cited By ~ 2

Author(s):

Suresh Kumar ◽

Shivani Kumar ◽

Heera Ram

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Docking ◽

Molecular Interaction ◽

Fibril Formation ◽

Amyloid Peptide ◽

Peptide Aggregation ◽

Aβ Peptide ◽

In Silico Studies

Amyloidogenesis is the process in which amyloid beta (Aβ) peptide aggregation results in plaque formation in central nervous system (CNS) are associated with many neurological diseases such as Alzheimer’s disease. The peptide aggregation initiated from peptide monomers results in formation of dimers, tetramers, fibrils, and protofibrils. The ability of allicin, a lipid-soluble volatile organosulfur biological compound, present in freshly crushed garlic ( Allium sativum L.) to inhibit fibril formation by the Aβ peptide in vitro was investigated in the present study. Inhibition of fibrillogenesis was measured by a Thioflavin T (ThT) fluorescence assay and visualized by transmission electron microscopy (TEM). The molecular interaction between allicin and Aβ peptide was also demonstrated by in silico studies. The results show that allicin strongly inhibited Aβ fibrils by 97% at 300 µM, compared with control (Aβ only) ( P < .001). These results were further validated by visual of fibril formation by transmission microscopy and molecular interaction of amyloid peptide with allicin by molecular docking. Aβ forms favourable hydrophobic interaction with Ile32, Met35, Val36, and Val39, and oxygen of allicin forms hydrogen bond with the amino acid residue Lys28. Allicin anti-amyloidogenic property suggests that this naturally occurring compound may have potential to ameliorate and prevent Alzheimer’s disease.

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Activation of the factor XII-driven contact system in Alzheimer’s disease patient and mouse model plasma

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1423764112 ◽

2015 ◽

Vol 112 (13) ◽

pp. 4068-4073 ◽

Cited By ~ 48

Author(s):

Daria Zamolodchikov ◽

Zu-Lin Chen ◽

Brooke A. Conti ◽

Thomas Renné ◽

Sidney Strickland

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Disease Patient ◽

Contact System ◽

Amyloid Peptide ◽

Factor Xii ◽

Contact Activation ◽

System Activation

Alzheimer’s disease (AD) is characterized by accumulation of the β-amyloid peptide (Aβ), which likely contributes to disease via multiple mechanisms. Increasing evidence implicates inflammation in AD, the origins of which are not completely understood. We investigated whether circulating Aβ could initiate inflammation in AD via the plasma contact activation system. This proteolytic cascade is triggered by the activation of the plasma protein factor XII (FXII) and leads to kallikrein-mediated cleavage of high molecular-weight kininogen (HK) and release of proinflammatory bradykinin. Aβ has been shown to promote FXII-dependent cleavage of HK in vitro. In addition, increased cleavage of HK has been found in the cerebrospinal fluid of patients with AD. Here, we show increased activation of FXII, kallikrein activity, and HK cleavage in AD patient plasma. Increased contact system activation is also observed in AD mouse model plasma and in plasma from wild-type mice i.v. injected with Aβ42. Our results demonstrate that Aβ42-mediated contact system activation can occur in the AD circulation and suggest new pathogenic mechanisms, diagnostic tests, and therapies for AD.

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The in vivo effect of oil palm phenolics (OPP) in atherogenic diet induced rat model of Alzheimer's Disease (AD)

The FASEB Journal ◽

10.1096/fasebj.29.1_supplement.271.8 ◽

2015 ◽

Vol 29 (S1) ◽

Author(s):

Yan Wu ◽

Vindhyaja Srirajavatsavai ◽

Kenechukwu Monplaisir ◽

Ravigadevi Sambanthamurthi ◽

Smiti Gupta

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Rat Model ◽

Oil Palm ◽

Atherogenic Diet ◽

Model Of Alzheimer’S Disease ◽

Oil Palm Phenolics

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Apolipoprotein E forms stable complexes with recombinant Alzheimer's disease β-amyloid precursor protein

Biochemical Journal ◽

10.1042/bj3250169 ◽

1997 ◽

Vol 325 (1) ◽

pp. 169-175 ◽

Cited By ~ 20

Author(s):

Cristina HAAS ◽

Pilar CAZORLA ◽

Carlos DE MIGUEL ◽

Fernando VALDIVIESO ◽

Jesús VÁZQUEZ

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Apolipoprotein E ◽

Senile Plaques ◽

Precursor Protein ◽

Amyloid Peptide ◽

Reducing Conditions ◽

Β Amyloid

Apolipoprotein E (apoE), a protein genetically linked to the incidence of Alzheimer's disease, forms SDS-stable complexes in vitro with β-amyloid peptide (Aβ), the primary component of senile plaques. In the present study, we investigated whether apoE was able to bind full-length Aβ precursor protein (APP). Using a maltose-binding-protein–APP fusion protein and human very-low-density lipoprotein (VLDL), we detected an interaction of apoE with APP that was inhibited by Aβ or anti-apoE antibody. Saturation-binding experiments indicated a single binding equilibrium with an apparent 1:1 stoichiometry and a dissociation constant of 15 nM. An interaction was also observed using apoE from cerebrospinal fluid or delipidated VLDL, as well as recombinant apoE. APP·apoE complexes were SDS-stable, and their formation was not inhibited by reducing conditions; however, they were dissociated by SDS under reducing conditions. ApoE·APP complexes formed high-molecular-mass aggregates, and competition experiments suggested that amino acids 14–23 of Aβ are responsible for complex-formation. Finally, no differences were found when studying the interaction of APP with apoE3 or apoE4. Taken together, our results demonstrate that apoE may form stable complexes with the Aβ moiety of APP with characteristics similar to those of complexes formed with isolated Aβ, and suggest the intriguing possibility that apoE–APP interactions may be pathologically relevant in vivo.

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Expression of proteins linked to Alzheimer’s disease in C6 rat glioma cells under the action of lipopolysaccharide (LPS), nimesulide, resveratrol and citalopram

Turkish Journal of Biochemistry ◽

10.1515/tjb-2020-0091 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Jorge Antonio Martínez-Díaz ◽

María Elena Hernández-Aguilar ◽

Fausto Rojas-Durán ◽

Deissy Herrera-Covarrubias ◽

Luis Isauro García-Hernández ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Western Blot ◽

Cell Model ◽

Glioma Cells ◽

C6 Glioma ◽

Amyloid Peptide ◽

C6 Glioma Cells ◽

Cox 2

AbstractObjectivesAlzheimer’s disease is complex and involves several proteins. Most affected are Tau protein and amyloid precursor protein (APP) which, when cleaved by the enzymes β-secretase (BACE1) and γ-secretase (Nicastrin), yield the amyloid peptide. Although these processes take place mainly in neurons, it is not exclusive of them, as glia cells also contribute to these processes. The objective of this study was to evaluate the effect of nimesulide, resveratrol and citalopram on C6 (glioma) cells when exposed to Lipopolysaccharide (LPS).MethodsExpression levels of the proteins APP, BACE1, COX-2, Nicastrin and Tau-p were evaluated by Western-blot and ELISA in C6 cells by effect of LPS, and the drugs citalopram, nimesulide and resveratrol.ResultsIt was found that LPS is able to hyperphosphorylate Tau in this cell model and the drugs decrease hyperphosphorylation. We also found that the drugs increase the expression of APP, decrease BACE1 and promote the expression of Nicastrin. COX-2 decreases its expression when nimesulide is used.ConclusionsOur results suggest that C6 cell line is useful to analyze the effect of pro-inflammatory molecules on tau phosphorylation and APP expression in vitro. The beneficial effect on the reduction of tau hyperphosphorylation shown by citalopram, nimesulide and resveratrol should be taken with caution due to the limitations of the present study and further research on these compounds is needed to determine their therapeutic use in neurodegenerative diseases such as Alzheimer’s disease.AmaçAlzheimer hastalığı karmaşıktır ve birkaç protein içerir. En çok etkilenenler, u-sekretaz (BACE1) ve γ-sekretaz (Nicastrin) enzimleri tarafından parçalandığında amiloid peptidi veren Tau proteini ve amiloid öncü proteinidir (APP). Bu süreçler esas olarak nöronlarda gerçekleşmesine rağmen, glia hücreleri de bu süreçlere katkıda bulunduğundan, bunlardan ayrı değildir. Amaç: Bu çalışmanın amacı, LPS’ye maruz kaldığında nimesulid, resveratrol ve sitalopramın C6 (glioma) hücreleri üzerindeki etkisini değerlendirmektir.Gereç ve YöntemAPP, BACE1, COX-2, Nicastrin ve Tau-p proteinlerinin ekspresyon seviyeleri, LPS’nin etkisi ile C6 hücrelerinde Western-blot ve ELISA ve sitalopram, nimesulid ve resveratrol ilaçları ile değerlendirildi.BulgularBu hücre modelinde LPS’nin Tau’yu hiperfosforilat edebildiği ve ilaçların hiperfosforilasyonu azalttığı bulundu. Ayrıca ilaçların APP ekspresyonunu arttırdığını, BACE1’i azalttığını ve Nicastrin ekspresyonunu teşvik ettiğini bulduk. Nimesulid kullanıldığında COX-2 ekspresyonunu azaltır.SonuçlarSonuçlarımız, pro-enflamatuar moleküllerin tau fosforilasyonu ve in vitro APP ekspresyonu üzerindeki etkisini analiz etmek için C6 hücre hattının yararlı olduğunu göstermektedir. Sitalopram, nimesulid ve resveratrol tarafından gösterilen tau hiperfosforilasyonunun azaltılması üzerindeki yararlı etki, mevcut çalışmanın sınırlamaları nedeniyle dikkatle alınmalı ve bu bileşikler üzerinde, Alzheimer hastalığı gibi nörodejeneratif hastalıklarda terapötik kullanımlarının belirlenmesi için daha fazla araştırmaya ihtiyaç vardır.

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Cerebrospinal fluid A beta 1-40 peptides increase in Alzheimer’s disease and are highly correlated with phospho-tau in control individuals

10.1101/2020.06.02.20119578 ◽

2020 ◽

Author(s):

Sylvain Lehmann ◽

Julien Dumurgier ◽

Xavier Ayrignac ◽

Cecilia Marelli ◽

Daniel Alcolea ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Statistical Tests ◽

Storage Conditions ◽

Amyloid Peptide ◽

Strong Positive Correlation ◽

Amyloid Pathology ◽

Highly Correlated

ABSTRACTBackground:Amyloid pathology, which is one of the characteristics of Alzheimer’s disease (AD), results from altered metabolism of the beta-amyloid peptide (Aβ) in terms of synthesis, clearance or aggregation. A decrease in cerebrospinal fluid (CSF) level Aβ 1-42 is evident in AD, and the CSF ratio Aβ 40 /Aβ 40 has recently been identified as one of the most reliable diagnostic biomarkers of amyloid pathology. Variations in inter-individual levels of Aβ 1-40 in the CSF have been observed in the past, but their origins remain unclear. In addition, the variation of Aβ 40 in the context of AD studied in several studies has yielded conflicting results.MethodsHere, we analyzed the levels of Aβ 1-40 using multicenter data obtained on 2466 samples from six different cohorts in which CSF was collected under standardized protocols, centrifugation and storage conditions. Tau and p-tau(181) concentrations were measured using commercially available in vitro diagnostic immunoassays. Concentrations of CSF Aβ 1-42 and Aβ 1-40 were measured by ELISA, xMAP technology, chemiluminescence immunoassay (CLIA) and mass spectrometry. Statistical analyses were calculated for parametric and non-parametric comparisons, linear regression, correlation and odds ratios. The statistical tests were adjusted for the effects of covariates (age, in particular).Results:Regardless of the analysis method used and the cohorts, a slight but significant age-independent increase in the levels of Aβ 40 in CSF was observed in AD. We also found a strong positive correlation between the levels of Aβ 40 and p-tau(181) in CSF, particularly in control patients.Conclusions:These results indicate that an increase in the baseline level of amyloid peptides, which are associated with an increase in p-tau(181), may be a biological characteristic of AD. This confirms the potential therapeutic value of lowering the baseline levels of Aβ 40 which, being elevated, can be considered a risk factor for the disease.

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Genistein and Galantamine Combinations Decrease β-Amyloid Peptide (1–42)–Induced Genotoxicity and Cell Death in SH-SY5Y Cell Line: an In Vitro and In Silico Approach for Mimic of Alzheimer’s Disease

Neurotoxicity Research ◽

10.1007/s12640-020-00243-8 ◽

2020 ◽

Vol 38 (3) ◽

pp. 691-706 ◽

Cited By ~ 1

Author(s):

Willian Orlando Castillo ◽

Nilza Velasco Palomino ◽

Catarina Satie Takahashi ◽

Silvana Giuliatti

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cell Death ◽

Cell Line ◽

In Silico ◽

Amyloid Peptide ◽

Β Amyloid ◽

Β Amyloid Peptide

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Physico-chemical methods for studing beta-amyloid aggregation

Biomeditsinskaya Khimiya ◽

10.18097/pbmc20156102203 ◽

2015 ◽

Vol 61 (2) ◽

pp. 203-218 ◽

Cited By ~ 3

Author(s):

S.P. Radko ◽

S.A. Khmeleva ◽

E.V. Suprun ◽

S.A. Kozin ◽

N.V. Bodoev ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gel Filtration ◽

Mass Spectrometric ◽

Correlation Spectroscopy ◽

Amyloid Peptide ◽

Detection Sensitivity ◽

Chemical Methods ◽

Physico Chemical

Alzheimer's disease is the most prevalent neurodegenerative pathology. According to the amyloid cascade hypothesis, a key event of the Alzheimer's disease pathogenesis is a transition of the b-amyloid peptide (Аb) from the monomeric form to the aggregated state. The mechanism of Аb aggregation is intensively studied in vitro, by means of synthetic peptides and various physico-chemical methods allowing evaluation of size, molecular structure, and morphology of the formed aggregates. The paper reviews both the well-known and recently introduced physico-chemical methods for analysis of Аb aggregation, including microscopу, optical and fluorescent methods, method of electron paramagnetic resonance, electrochemical and electrophoretic methods, gel-filtration, and mass spectrometric methods. Merits and drawbacks of the methods are discussed. The unique possibility to simultaneously observe Аb monomers as well oligomers and large aggregates by means of atomic force microscopy or fluorescence correlation spectroscopy is emphasized. The high detection sensitivity of the latter method, monitoring the aggregation process in Аb solutions at low peptide concentrations is underlined. Among mass spectrometric methods, the ion mobility mass spectrometry is marked out as a method enabling to obtain information about both the spectrum of Аb oligomers and their structure. It is pointed out that the use of several methods giving the complementary data about Аb aggregates is the best experimental approach to studying the process of b-amyloid peptide aggregation in vitro.

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Chi3l1/YKL-40 is controlled by the astrocyte circadian clock and regulates neuroinflammation and Alzheimer’s disease pathogenesis

Science Translational Medicine ◽

10.1126/scitranslmed.aax3519 ◽

2020 ◽

Vol 12 (574) ◽

pp. eaax3519

Author(s):

Brian V. Lananna ◽

Celia A. McKee ◽

Melvin W. King ◽

Jorge L. Del-Aguila ◽

Julie M. Dimitry ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Circadian Clock ◽

Amyloid Plaque ◽

Amyloid Peptide ◽

Plaque Burden ◽

Clock Proteins ◽

Amyloid Accumulation ◽

Β Amyloid Peptide

Regulation of glial activation and neuroinflammation are critical factors in the pathogenesis of Alzheimer’s disease (AD). YKL-40, a primarily astrocytic protein encoded by the gene Chi3l1, is a widely studied cerebrospinal fluid biomarker that increases with aging and early in AD. However, the function of Chi3l1/YKL-40 in AD is unknown. In a cohort of patients with AD, we observed that a variant in the human CHI3L1 gene, which results in decreased CSF YKL-40 expression, was associated with slower AD progression. At baseline, Chi3l1 deletion in mice had no effect on astrocyte activation while modestly promoting microglial activation. In a mouse APP/PS1 model of AD, Chi3l1 deletion decreased amyloid plaque burden and increased periplaque expression of the microglial lysosomal marker CD68, suggesting that Chi3l1 may suppress glial phagocytic activation and promote amyloid accumulation. Accordingly, Chi3l1 knockdown increased phagocytosis of zymosan particles and of β-amyloid peptide in both astrocytes and microglia in vitro. We further observed that expression of Chi3l1 is regulated by the circadian clock, as deletion of the core clock proteins BMAL1 or CLOCK/NPAS2 strongly suppresses basal Chi3l1 expression, whereas deletion of the negative clock regulators PER1/PER2 increased Chi3l1 expression. Basal Chi3l1 mRNA was nonrhythmic because of a long mRNA half-life in astrocytes. However, inflammatory induction of Chi3l1 was gated by the clock. Our findings reveal Chi3l1/YKL-40 as a modulator of glial phagocytic activation and AD pathogenesis in both mice and humans and suggest that the astrocyte circadian clock regulates inflammatory Chi3l1 induction.

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