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Tau phosphorylation

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https://www.readbyqxmd.com/read/28726316/deprotonation-states-of-the-two-active-site-water-molecules-regulate-the-binding-of-protein-phosphatase-5-with-its-substrate-a-molecular-dynamics-study
#1
Lingyun Wang, Feng Yan
Protein phosphatase 5 (PP5), mainly localized in human brain, can dephosphorylate tau protein whose high level of phosphorylation is related to Alzheimer's disease. Similar to other protein phosphatases, PP5 has a conserved motif in the catalytic domain that contains two binding sites for manganese (Mn(2+) ) ions. Structural data indicate that two active site water molecules, one bridging the two Mn(2+) ions and the other terminally coordinated with one of the Mn(2+) ions (Mn1), are involved in catalysis. Recently, a density functional theory study revealed that the two water molecules can be both deprotonated to keep a neutral active site for catalysis...
July 20, 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/28720530/downregulation-of-protein-phosphatase-2a-by-apolipoprotein-e-implications-for-alzheimer-s-disease
#2
Veena Theendakara, Dale E Bredesen, Rammohan V Rao
The apolipoprotein E ε4 allele is the single most important genetic risk factor associated with Alzheimer's disease (AD). Tau phosphorylation and hyperphosphorylation is an underlying feature of AD and is regulated by specific kinases and phosphatases. Among phosphatases, protein phosphatase 2A (PP2A) is the principal tau dephosphorylating enzyme in the brain. Several abnormalities of PP2A have been reported in AD, including among others decreased protein levels of PP2A, decreased mRNA and protein levels of the catalytic subunit PP2AC and variable regulatory B subunits and reduced methylation of the catalytic subunit, all of which results in disruption of the PP2A phosphatase activity...
July 15, 2017: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/28719018/ante-mortem-csf-tau-levels-correlate-with-post-mortem-tau-pathology-in-ftld
#3
D J Irwin, A Lleó, S X Xie, C T McMillan, D Wolk, E B Lee, V M Van Deerlin, L M Shaw, J Q Trojanowski, M Grossman
OBJECTIVE: To test the hypotheses that 1) antemortem cerebrospinal fluid tau levels correlate with postmortem tau pathology in frontotemporal lobar degeneration and 2) tauopathy patients have higher phosphorylated-tau levels compared to TDP-43 proteinopathy patients while accounting for Alzheimer's disease co-pathology. METHODS: Patients had autopsy-confirmed frontotemporal lobar degeneration with tauopathy (n=31), TDP-43 proteinopathy (n=49), or Alzheimer's disease (n=26) with antemortem cerebrospinal fluid...
July 18, 2017: Annals of Neurology
https://www.readbyqxmd.com/read/28717968/deletion-of-type-2-cannabinoid-receptor-induces-alzheimer-s-disease-like-tau-pathology-and-memory-impairment-through-ampk-gsk3%C3%AE-pathway
#4
Lin Wang, Bing-Jin Liu, Yun Cao, Wei-Qi Xu, Dong-Sheng Sun, Meng-Zhu Li, Fang-Xiao Shi, Man Li, Qing Tian, Jian-Zhi Wang, Xin-Wen Zhou
Although several studies have shown that type-2 cannabinoid receptor (CB2R) is involved in Alzheimer's disease (AD) pathology, the effects of CB2R on AD-like tau abnormal phosphorylation and its underlying mechanism remain unclear. Herein, we employed the CB2R(-/-) mice as the animal model to explore roles of CB2R in regulating tau phosphorylation and brain function. We found that CB2R(-/-) mice display AD-like tau hyperphosphorylation, hippocampus-dependent memory impairment, increase of GSK3β activity, decrease of AMPK and Sirt1 activity and mitochondria dysfunction...
July 17, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28714354/is-cerebral-microbleed-prevalence-relevant-as-a-biomarker-in-amnestic-mild-cognitive-impairment-and-mild-alzheimer-s-disease
#5
Ana Gb Rabelo, Camila Vl Teixeira, Thamires Nc Magalhães, Ana Flávia Mk Carletti-Cassani, Augusto Cs Amato Filho, Helena Pg Joaquim, Leda L Talib, Orestes Forlenza, Patrícia Ao Ribeiro, Rodrigo Secolin, Iscia Lopes-Cendes, Fernando Cendes, Marcio Lf Balthazar
Introduction The search for a reliable neuroimaging biomarker in Alzheimer's disease is a matter of intense research. The presence of cerebral microbleeds seems to be a potential biomarker. However, it is not clear if the presence of microbleeds has clinical usefulness to differentiate mild Alzheimer's disease and amnestic mild cognitive impairment from normal aging. We aimed to verify if microbleed prevalence differs among three groups: mild Alzheimer's disease, amnestic mild cognitive impairment due to Alzheimer's disease, and normal controls...
January 1, 2017: Neuroradiology Journal
https://www.readbyqxmd.com/read/28713242/the-distance-between-n-and-c-termini-of-tau-and-of-ftdp-17-mutants-is-modulated-by-microtubule-interactions-in-living-cells
#6
Cristina Di Primio, Valentina Quercioli, Giacomo Siano, Matteo Rovere, Branislav Kovacech, Michal Novak, Antonino Cattaneo
The microtubule (MT)-associated protein Tau is a natively unfolded protein, involved in a number of neurodegenerative disorders, collectively called tauopathies, aggregating in neurofibrillary tangles (NFT). It is an open question how the conversion from a MT bound molecule to an aggregation-prone Tau species occurs and, also, if and how tauopathy-related mutations affect its behavior in the cell. To address these points, we exploited a genetically encoded FRET sensor based on the full length Tau protein, to monitor in real time Tau conformational changes in different conditions in live cells...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28712706/discovery-of-novel-2-4-aryl-2-methylpiperazin-1-yl-pyrimidin-4-ones-as-glycogen-synthase-kinase-3%C3%AE-inhibitors
#7
Toshiyuki Kohara, Kazuki Nakayama, Kazutoshi Watanabe, Shin-Ichi Kusaka, Daiki Sakai, Hiroshi Tanaka, Kenji Fukunaga, Shinji Sunada, Mika Nabeno, Ken-Ichi Saito, Jun-Ichi Eguchi, Akiko Mori, Shinji Tanaka, Tomoko Bessho, Keiko Takiguchi-Hayashi, Takashi Horikawa
We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3β inhibitors from our promising compounds containing a 3-methylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3β inhibitors. SAR studies focused on the nitrogen atom of the piperazine moiety revealed that a phenyl group afforded potent inhibitory activity toward GSK-3β. Docking studies indicated that the phenyl group on the piperazine nitrogen atom and the methyl group on the piperazine make cation-π and CH-π interactions with GSK-3β respectively...
July 5, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28711868/human-ttbk1-ttbk2-and-mark1-kinase-toxicity-in-drosophila-melanogaster-is-exacerbated-by-co-expression-of-human-tau
#8
Josefin Fernius, Annika Starkenberg, Malgorzata Pokrzywa, Stefan Thor
Tau protein is involved in numerous human neurodegenerative diseases, and Tau hyper-phosphorylation has been linked to Tau aggregation and toxicity. Previous studies have addressed toxicity and phospho-biology of human Tau (hTau) in Drosophila melanogaster However, hTau transgenes have most often been randomly inserted in the genome, thus making it difficult to compare between different hTau isoforms and phospho-mutants. In addition, many studies have expressed hTau also in mitotic cells, causing non-physiological toxic effects...
July 15, 2017: Biology Open
https://www.readbyqxmd.com/read/28711506/sodium-selenate-activated-wnt-%C3%AE-catenin-signaling-and-repressed-amyloid-%C3%AE-formation-in-a-triple-transgenic-mouse-model-of-alzheimer-s-disease
#9
Na Jin, Huazhang Zhu, Xiao Liang, Wei Huang, Qingguo Xie, Peng Xiao, Jiazuan Ni, Qiong Liu
Accumulating evidences show that selenium dietary intake is inversely associated with the mortality of Alzheimer's disease (AD). Sodium selenate has been reported to reduce neurofibrillary tangles (NFT) in the tauopathic mouse models, but its effects on the Wnt/β-catenin signaling pathway and APP processing remain unknown during AD formation. In this paper, triple transgenic AD mice (3×Tg-AD) had been treated with sodium selenate in drinking water for 10month before the detection of hippocampal pathology...
July 12, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28710906/upward-drift-in-cerebrospinal-fluid-amyloid-%C3%AE-42-assay-values-for-more-than-10%C3%A2-years
#10
Suzanne E Schindler, Courtney L Sutphen, Charlotte Teunissen, Lena M McCue, John C Morris, David M Holtzman, Sandra D Mulder, Philip Scheltens, Chengjie Xiong, Anne M Fagan
INTRODUCTION: The best-established cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease are levels of amyloid-β 42 (Aβ42), total tau (tau), and phosphorylated tau 181 (ptau). We examined whether a widely used commercial immunoassay for CSF Aβ42, tau, and ptau provided stable measurements for more than ∼10 years. METHODS: INNOTEST assay values for CSF Aβ42, tau, and ptau from Washington University in St. Louis and VU Medical Center, Amsterdam, were evaluated...
July 12, 2017: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
https://www.readbyqxmd.com/read/28710841/accelerated-kindling-epileptogenesis-in-tg4510-tau-transgenic-mice-but-not-in-tau-knockout-mice
#11
Shijie Liu, Yu Shen, Sandy R Shultz, Anne Nguyen, Christopher Hovens, Paul A Adlard, Ashley I Bush, Jianxiong Chan, Patrick Kwan, Terence J O'Brien, Nigel C Jones
The biologic processes underlying epileptogenesis following a brain insult are not fully understood, but several lines of evidence suggest that hyperphosphorylation of tau may be an important factor in these processes. To provide further insight into the causal relationship between tau and epileptogenesis, this study applied amygdala kindling to rTg4510 mice that, concurrent with other pathologies, overexpress phosphorylated tau, tau knockout mice, or their respective wild-type controls. Mice were electrically stimulated twice daily, 5 days per week for 3 weeks...
July 15, 2017: Epilepsia
https://www.readbyqxmd.com/read/28709620/synthesis-and-anti-diabetic-activity-of-new-n-n-dimethylphenylenediamine-derivatized-nitrilotriacetic-acid-vanadyl-complexes
#12
Xia Niu, Jichun Yang, Xiaoda Yang
Vanadium compounds are promising anti-diabetic agents. However, reducing the metal toxicity while keeping/improving the hypoglycemic effect is still a big challenge towards the success of anti-diabetic vanadium drugs. To improve the therapeutic potency using the anti-oxidative strategy, we synthesized new N,N-dimethylphenylenediamine (DMPD)-derivatized nitrilotriacetic acid vanadyl complexes ([VO(dmada)]). The in vitro biological evaluations revealed that the DMPD-derivatized complexes showed improved antioxidant capacity and lowered cytotoxicity on HK-2 cells than bis(maltolato)oxidovanadium (IV) (BMOV)...
July 8, 2017: Journal of Inorganic Biochemistry
https://www.readbyqxmd.com/read/28709448/no-added-diagnostic-value-of-non-phosphorylated-tau-fraction-p-taurel-in-csf-as-a-biomarker-for-differential-dementia-diagnosis
#13
Joery Goossens, Maria Bjerke, Hanne Struyfs, Ellis Niemantsverdriet, Charisse Somers, Tobi Van den Bossche, Sara Van Mossevelde, Bart De Vil, Anne Sieben, Jean-Jacques Martin, Patrick Cras, Johan Goeman, Peter Paul De Deyn, Christine Van Broeckhoven, Julie van der Zee, Sebastiaan Engelborghs
BACKGROUND: The Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers Aβ1-42, t-tau, and p-tau181 overlap with other diseases. New tau modifications or epitopes, such as the non-phosphorylated tau fraction (p-taurel), may improve differential dementia diagnosis. The goal of this study is to investigate if p-taurel can improve the diagnostic performance of the AD CSF biomarker panel for differential dementia diagnosis. METHODS: The study population consisted of 45 AD, 45 frontotemporal lobar degeneration (FTLD), 45 dementia with Lewy bodies (DLB), and 21 Creutzfeldt-Jakob disease (CJD) patients, and 20 cognitively healthy controls...
July 14, 2017: Alzheimer's Research & Therapy
https://www.readbyqxmd.com/read/28708069/distinct-mechanisms-underlying-resveratrol-mediated-protection-from-types-of-cellular-stress-in-c6-glioma-cells
#14
John C Means, Bryan C Gerdes, Peter Koulen
The polyphenolic phytostilbene, trans-resveratrol, is found in high amounts in several types and tissues of plants, including grapes, and has been proposed to have beneficial effects in the central nervous system due to its activity as an antioxidant. The objective of the present study was to identify the mechanisms underlying the protective effects of resveratrol under conditions of oxidative stress or DNA damage, induced by the extracellularly applied oxidant, tert-butyl hydrogen peroxide, or UV-irradiation, respectively...
July 14, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28707717/an-autopsied-case-of-corticobasal-degeneration-presenting-with-frontotemporal-dementia-followed-by-myoclonus
#15
Yasushi Iwasaki, Keiko Mori, Masumi Ito, Maya Mimuro, Mari Yoshida
A Japanese woman developed frontotemporal dementia (FTD)-like symptoms of abnormal behavior, such as stereotyped behavior and disinhibition. The patient developed these symptoms at the age of 59 years, although aphasia symptoms were not apparent at early disease stages. Progressive parkinsonism was dominant on the left side, and conspicuous myoclonus was recognized in the late disease stage. MRI indicated severe, right side-dominant frontotemporal lobe atrophy with white matter degeneration. Brainstem and cerebellar atrophy were also observed...
July 14, 2017: Neuropathology: Official Journal of the Japanese Society of Neuropathology
https://www.readbyqxmd.com/read/28704727/nrf2-deficiency-replicates-transcriptomic-changes-in-alzheimer-s-patients-and-worsens-app-and-tau-pathology
#16
Ana I Rojo, Marta Pajares, Patricia Rada, Angel Nuñez, Alejo J Nevado-Holgado, Richard Killik, Fred Van Leuven, Elena Ribe, Simon Lovestone, Masayuki Yamamoto, Antonio Cuadrado
Failure to translate successful neuroprotective preclinical data to a clinical setting in Alzheimer's disease (AD) indicates that amyloidopathy and tauopathy alone provide an incomplete view of disease. We have tested here the relevance of additional homeostatic deviations that result from loss of activity of transcription factor NRF2, a crucial regulator of multiple stress responses whose activity declines with ageing. A transcriptomic analysis demonstrated that NRF2-KO mouse brains reproduce 7 and 10 of the most dysregulated pathways of human ageing and AD brains, respectively...
July 5, 2017: Redox Biology
https://www.readbyqxmd.com/read/28701950/cerebrospinal-fluid-a%C3%AE-43-is-reduced-in-early-onset-compared-to-late-onset-alzheimer-s-disease-but-has-similar-diagnostic-accuracy-to-a%C3%AE-42
#17
Camilla Lauridsen, Sigrid B Sando, Ina Møller, Guro Berge, Precious K Pomary, Gøril R Grøntvedt, Øyvind Salvesen, Geir Bråthen, Linda R White
Background: Amyloid beta 1-43 (Aβ43) may be a useful additional biomarker for diagnosing Alzheimer's disease (AD). We have investigated cerebrospinal fluid (CSF) levels of Aβ43 in patients with early-onset AD in contrast to levels in late-onset AD. For comparison, in addition to the 'core' biomarkers, several other analytes were also determined [YKL-40, neurofilament light (NF-L), glial fibrillary acidic protein (GFAP), and progranulin]. Material and Methods: Cerebrospinal fluid samples were obtained from patients with early-onset AD (age ≤ 62, n = 66), late-onset AD (age ≥ 68, n = 25), and groups of cognitively intact individuals (age ≤ 62, n = 41, age ≥ 68, n = 39)...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/28699522/targeting-human-astrocytes-calcium-sensing-receptors-for-treatment-of-alzheimer-s-disease
#18
Anna Chiarini, Ubaldo Armato, James F Whitfield, Ilaria Dal Pra
Understanding the pathophysiology of Alzheimer's disease (AD) in the principal human neural cells is necessary for finding therapeutics for this illness. To help do this, we have been using freshly cultured functionally normal cerebral cortical adult human astrocytes (NAHAs) and postnatal neurons. The findings show that amyloid-β oligomers (Aβ-os) binding to calcium-sensing receptors (CaSRs) on NAHAs and neuron surfaces trigger signals capable of driving AD pathogenesis. This Aβ•CaSR signalling shifts the amyloid precursor protein (APP) from its α-secretase shedding producing neurotrophic/neuroprotective soluble (s)APPα to its β-secretase cleaving engendering AD-driving Aβ42/Aβ42-os peptides...
July 10, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28694093/functional-analyses-of-major-cancer-related-signaling-pathways-in-alzheimer-s-disease-etiology
#19
REVIEW
Jianping Guo, Ji Cheng, Brian J North, Wenyi Wei
Alzheimer's disease (AD) is an aging-related neurodegenerative disease and accounts for majority of human dementia. The hyper-phosphorylated tau-mediated intracellular neurofibrillary tangle and amyloid β-mediated extracellular senile plaque are characterized as major pathological lesions of AD. Different from the dysregulated growth control and ample genetic mutations associated with human cancers, AD displays damage and death of brain neurons in the absence of genomic alterations. Although various biological processes predominately governing tumorigenesis such as inflammation, metabolic alteration, oxidative stress and insulin resistance have been associated with AD genesis, the mechanistic connection of these biological processes and signaling pathways including mTOR, MAPK, SIRT, HIF, and the FOXO pathway controlling aging and the pathological lesions of AD are not well recapitulated...
July 7, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28692877/association-between-cerebrospinal-fluid-and-plasma-neurodegeneration-biomarkers-with-brain-atrophy-in-alzheimer-s-disease
#20
Joana B Pereira, Eric Westman, Oskar Hansson
The aggregation and deposition of amyloid-β (Aβ) peptides into plaques is an early event in Alzheimer's disease (AD), which is followed by different aspects of neurodegeneration that can be measured in the cerebrospinal fluid (CSF) or plasma using neurofilament light (NFL), neurogranin (Ng), total Tau (T-Tau), and phosphorylated tau (P-Tau) levels. The relationship between these biomarkers and regional brain atrophy across the different stages of AD remains largely unexplored. In this study, we assessed whether NFL, Ng, T-Tau, and P-Tau levels in CSF and NFL in plasma are associated with cortical thinning and subcortical volume loss in cognitively normal, mild cognitive impairment, and AD subjects with and without Aβ pathology...
June 17, 2017: Neurobiology of Aging
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