Effects of antibodies to phosphorylated and non-phosphorylated tau on in vitro tau phosphorylation at Serine-199: Preliminary report

Loeffler, David A.; Smith, Lynnae M.; Klaver, Andrea C.; Martić, Sanela

doi:10.1016/j.exger.2015.04.010

Cited by 9 publications

(10 citation statements)

References 19 publications

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“…Alzheimer’s disease (AD) is the most common form of dementia worldwide but the underlying mechanisms leading to AD are still not fully understood. Two major hallmarks appear to be characteristic for AD: the accumulation of extracellular beta-amyloid (Aβ) plaques and the hyperphosphorylation of tau leading to the formation of intraneuronal neurofibrillary tangles (NFTs; Loeffler et al, 2015 ; Ahn et al, 2016 ). The most prominent hypothesis for AD is the Aβ cascade, where a successive cleavage of the amyloid precursor protein (APP) and an imbalance between the clearance and production of Aβ leads to an abnormal accumulation of Aβ in the brain.…”

Section: Introductionmentioning

confidence: 99%

Differential Hyperphosphorylation of Tau-S199, -T231 and -S396 in Organotypic Brain Slices of Alzheimer Mice. A Model to Study Early Tau Hyperphosphorylation Using Okadaic Acid

Foidl

Humpel

2018

Front. Aging Neurosci.

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of the brain, characterized by extracellular aggregation of beta-amyloid (Aβ) and hyperphosphorylation of tau causing intraneuronal neurofibrillary tangles (NFTs). There is urgent need to study the interactions between Aβ and tau, especially to solve the question of the pathological cascade. In the present study, we aim to develop a model of organotypic brain slices in which both plaque and tau pathology can be examined. Organotypic brain slices (150 μm thick, coronal, at the hippocampal level) from adult (9 month) wildtype (WT, C57BL/6N) and transgenic AD mice (TG, APP_SweDI) were cultured for 2 weeks. To induce tau hyperphosphorylation 100 nM okadaic acid (OA), 10 μM wortmannin (WM) or both were added to the slices. Hyperphosphorylation of tau was tested at tau-S199, tau-T231 and tau-S396 using Western blot. Our data show that in TG mice with plaques a 50 kDa fragment of tau-S396 was hyperphosphorylated and that OA induced hyperphosphorylation of tau-S199. In WT mice (without plaques) OA caused hyperphosphorylation of a 50 kDa and a 38 kDa tau-T231 form and a 25 kDa sdftau-S396 fragment. The N-methyl-D-aspartate (NMDA) antagonist MK801 (1 μM) did not block these effects. Immunohistochemistry showed diffuse increased tau-S396 and tau-T231-like immunoreactivities at the hippocampal level but no formation of NFTs. Confocal microscopy indicated, that pTau-T231 was preferentially located in cytoplasma surrounding nuclei whereas pTau-S396 was found mainly in nerve fibers and strongly associated with plaques. In conclusion we provide a novel in vitro model to study both plaque and tau hyperphosphorylation but not NFTs, which could be useful to study pathological processes in AD and to screen for drugs.

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Section: Introductionmentioning

confidence: 99%

Differential Hyperphosphorylation of Tau-S199, -T231 and -S396 in Organotypic Brain Slices of Alzheimer Mice. A Model to Study Early Tau Hyperphosphorylation Using Okadaic Acid

Foidl

Humpel

2018

Front. Aging Neurosci.

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“…Reaksi radikal bebas menyebabkan kematian neuron menyebar ke sel-sel di dekatnya semakin progresif, yang dapat dilihat dari gambaran imunohistokimia jaringan otak. [7][8] Pencegahan CTE selama ini hanya memakai helm sebagai alat pelindung diri pada benturan kepala, seperti pada permainan rugbi atau hoki, namun belum efektif dan tidak bisa meminimalisir terjadinya CTE. Hal ini karena benturan yang mampu dikompensasi manusia adalah sebesar 60 Gforce, sedangkan benturan yang dialami para atlet lebih dari 60 Gforce, bahkan sampai 100 Gforce.…”

Section: Pendahuluanunclassified

Pemanfaatan Alpha Lipoic Acid Sebagai Inhibitor Degenerasi Protein Tau Untuk Pencegahan Chronic Traumatic Encephalopathy

Gunawan

Utami

Putri

et al. 2017

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THE USE OF ALPHA LIPOIC ACID AS TAU PROTEIN DEGENERATION INHIBITOR ON PREVENCE CHRONIC TRAUMATIC ENCEPHALOPATHYABSTRACTIntroduction: Chronic traumatic encephalopathy (CTE) is progressive neurodegenerative syndrome caused by repeated blunt object injury affects the head. This condition results in degeneration of tau, a protein that can help stabilize and support certain structures in brain’s cells, including internal transport system of the brain’s cell. Repeated injuries cause the degeneration of tau proteins that proteins misfold and change their form and then become free radicals cause neuron death. Alpha lipoic acid (ALA) is one of the antioxidant can bind free radicals and regenerate antioxidant vitamin C, vitamin E, and coenzyme Q10.Aim: To exam the effectiveness of alpha lipoic acid to inhibit the degeneration of tau protein in immunohistochemistry experimental animals’s brain.Methods: Experimental study in vivo of CTE model in rat by dropped 245g load on the head at 35cm height. 28 rats were randomly assigned to 7 groups; normal group without treatment, negative control group is given NaCl 0.9% 1.5mL, positive control group is given citicholine 6.75mg, group A is given ALA 1.0125mg, group B is given ALA 2.025mg, group C is given ALA 4.05mg, group D is given ALA 8.1mg and received 30 days CTE treatment. Experiment was conducted in May 2017 at Medical Faculty University of Jember. Tau protein degeneration were scored immunohistochemically.Results: Group D showed the closest to normal, while group A showed most tau protein degeneration (190.25±26.89) compared to normal group (53.25±43.39). Group D also showed lower tau protein score compared to positive control significantly.Discussion: Alpha lipoic acid is able to inhibit the progression of tau protein degeneration on immunohistochemistry staining of animal’s brains in CTE model.Keyword: Alpha lipoic acid, chronic traumatic encephalopathy, tau proteinABSTRAKPendahuluan: Chronic traumatic encephalopathy (CTE) adalah sindrom neurodegeneratif progresif akibat cedera berulang benda tumpul yang mengenai kepala. Cedera berulang tersebut menyebabkan degenerasi protein tau, yaitu protein yang dapat membantu menstabilkan dan mendukung struktur tertentu dalam sel otak, termasuk sel dari sistem transportasi internal. Akibatnya, protein tau gagal melipat dan mengubah bentuk, sehingga menjadi radikal bebas yang dapat menye- babkan kematian neuron. Alpha lipoic acid (ALA) adalah salah satu senyawa antioksidan yang mampu mengikat radikal bebas dan meregenerasi antioksidan vitamin C, vitamin E, dan koenzim Q 10.Tujuan: Mengetahui efektivitas pemberian alpha lipoic acid dalam menghambat progresivitas degenerasi protein tau pada gambaran imunohistokimia otak hewan coba.Metode: Studi eksperimental in vivo model CTE pada tikus dengan dijatuhi beban 245g di kepala pada ketinggian35cm. Terdapat 28 tikus yang dibagi menjadi 7 kelompok, yaitu: kelompok normal tanpa perlakuan, kelompok kontrol (-) diberikan NaCl 1,5mL, kontrol (+) diberikan sitikolin 6,75mg, kelompok A diberikan ALA 1,0125mg, kelompok B diberi- kan ALA 2,025mg, kelompok C diberikan ALA 4,05mg, serta kelompok D diberikan ALA 8,1mg dan mendapat perlakuan CTE selama 30 hari. Penelitian dilakukan pada bulan Mei 2017 di Fakultas Kedokteran Universitas Jember. Pemeriksaan skor degenerasi protein tau berdasarkan gambaran imunohistokimia.Hasil: Kelompok D dengan dosis tertinggi 8,1mg merupakan gambaran degenerasi protein tau paling sedikit mendekati normal, sedangkan kelompok A dengan dosis terendah 1,0125mg merupakan gambaran degenerasi protein tau paling banyak (190,25±26,89), jauh lebih tinggi dibandingkan kelompok normal (53,25±43,39). Demikian pula kelompok D dengan kontrol positif menunjukkan skor degenerasi protein tau kelompok D lebih rendah dibandingkan dengan kontrol positif secara bermakna.Diskusi: Pemberian ALA dosis tinggi mampu menghambat progresivitas degenerasi protein tau pada gambaran imunohistokimia otak hewan coba yang mengalami cedera kepala berulang.Kata kunci: Alpha lipoic acid, chronic traumatic encephalopathy, protein tau

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“…to study the effect of protein phosphorylation on an interaction with a third protein [43] , [44] . In most papers, the in vitro kinase reactions are intended to characterize the phosphorylation event itself – to determine parameters such as kinetics, kinase substrate specificity and target-site identification [45] , [46] , [47] , [48] .…”

Section: Introductionmentioning

confidence: 99%

“…Baudin and Müller [45] , [46] , [47] , [48] took a different approach and in bacteria co-expressed both a kinase domain and a STAT protein for in vivo phosphorylation. Using this approach, they purified Tyr-phosphorylated STAT proteins, which were used to assess the binding of STAT proteins to specific DNA sequences by electrophoretic mobility shift assay (EMSA).…”

Section: Introductionmentioning

confidence: 99%

Exploring protein phosphorylation by combining computational approaches and biochemical methods

Pérez‐Mejías

Velázquez‐Cruz

Guerra‐Castellano

et al. 2020

Computational and Structural Biotechnology Journal

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Effects of antibodies to phosphorylated and non-phosphorylated tau on in vitro tau phosphorylation at Serine-199: Preliminary report

Cited by 9 publications

References 19 publications

Differential Hyperphosphorylation of Tau-S199, -T231 and -S396 in Organotypic Brain Slices of Alzheimer Mice. A Model to Study Early Tau Hyperphosphorylation Using Okadaic Acid

Differential Hyperphosphorylation of Tau-S199, -T231 and -S396 in Organotypic Brain Slices of Alzheimer Mice. A Model to Study Early Tau Hyperphosphorylation Using Okadaic Acid

Pemanfaatan Alpha Lipoic Acid Sebagai Inhibitor Degenerasi Protein Tau Untuk Pencegahan Chronic Traumatic Encephalopathy

Exploring protein phosphorylation by combining computational approaches and biochemical methods

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