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Tau oligomers

Nasimudeen R Jabir, Fayaz Rahman Khan, Shams Tabrez
Alzheimer's disease (AD) is a progressive irreversible neurodegenerative disorder characterized by excessive deposition of β-amyloid (Aβ) oligomers, and neurofibrillary tangles (NFTs), comprising of hyperphosphorylated tau proteins. The cholinergic system has been suggested as the earliest and most affected molecular mechanism that describes AD pathophysiology. Moreover, cholinesterase inhibitors (ChEIs) are the potential class of drugs that can amplify cholinergic activity to improve cognition and global performance and reduce psychiatric and behavioral disturbances...
May 16, 2018: CNS Neuroscience & Therapeutics
Bonnie J Berry, Alec S T Smith, Christopher J Long, Candace C Martin, James J Hickman
Alzheimer's disease (AD) is characterized by slow, progressive neurodegeneration leading to severe neurological impairment, but current drug development efforts are limited by the lack of robust, human-based disease models. Amyloid-β (Aβ) is known to play an integral role in AD progression as it has been shown to interfere with neurological function. However, studies into AD pathology commonly apply Aβ to neurons for short durations at non-physiological concentrations to induce an exaggerated dysfunctional phenotype...
May 10, 2018: ACS Chemical Neuroscience
Hui Chen, Simu Liu, Shuiming Li, Jierui Chen, Jiazuan Ni, Qiong Liu
Abnormal accumulation of tau protein into oligomers contributes to neuronal dysfunction. Reduction of tau level is potentially able to prevent its accumulation. Here we uncover a critical role of the free thiol at Cys-322 in determining tau stability. We found that the application of thiol-blocking agents like NEM or MMTS blocks this thiol, by which it destabilizes tau protein and prevents its oligomer formation. Furthermore, we identified a tau-interacting protein, selenoprotein W, which attenuates tau accumulation by forming disulfide linkage between SelW Cys-37 and tau Cys-322...
May 1, 2018: ACS Chemical Neuroscience
Karishma Bhasne, Sanjana Sebastian, Neha Jain, Samrat Mukhopadhyay
Amyloidogenic intrinsically disordered proteins, α-synuclein and tau are linked to Parkinson's disease and Alzheimer's disease, respectively. A body of evidences suggests that α-synuclein and tau, both present in the presynaptic nerve terminals, co-aggregate in many neurological ailments. The molecular mechanism of α-synuclein-tau hetero-assembly is poorly understood. Here we show that amyloid formation is synergistically facilitated by heterotypic association mediated by binding-induced misfolding of both α-synuclein and tau K18...
April 25, 2018: Journal of Molecular Biology
Aristo Vojdani, Elroy Vojdani, Evan Saidara, Datis Kharrazian
As early as the 1980s, molecular virologist Ruth Itzhaki began to investigate if there was a causal connection between infections and neurodegenerative disorder. Although the theory has yet to be universally embraced, in 2016 Itzhaki and 33 other scientists from all over the world published a review article in this very journal presenting evidence for the causal role of pathogens in Alzheimer's disease (AD). Exactly how and in what way pathogens affect the induction of AD has yet to be determined, but one possible answer may involve the cross-reactivity of different pathogens with amyloid-β (Aβ)...
2018: Journal of Alzheimer's Disease: JAD
Hidenobu Shozawa, Tatsunori Oguchi, Mayumi Tsuji, Satoshi Yano, Yuji Kiuchi, Kenjiro Ono
Alzheimer disease (AD) is the most common type of dementia, and is currently incurable. The efficacy of existing treatments for AD such as acetylcholinesterase inhibitors is limited to symptom improvement. Research on disease-modifying therapies (DMTs) has conventionally focused on amelioration of CNS pathogenesis. Two neuropathological changes correlate strongly with AD, the appearance of neurofibrillary tangles containing the microtubule-associated protein tau and extracellular amyloid deposits containing amyloid β-protein (Aβ)...
April 20, 2018: Neuroscience Letters
Die Pu, Yuxing Zhao, Jinliang Chen, Yue Sun, Ankang Lv, Shiyu Zhu, Cheng Luo, Kexiang Zhao, Qian Xiao
Type 2 diabetes mellitus (T2DM)-associated oxidative stress contributes to cognitive deficiencies and Alzheimer's disease (AD). Sulforaphane (SFN) is a pharmacological activator of Nrf2 that provokes Nrf2-mediated intracellular defenses, including antioxidant and anti-inflammatory responses, under oxidative stress (OS) conditions. This study investigated the effects of SFN on DM-related cognitive decline and its potential mechanisms. Morris water maze (MWM) tests showed that SFN (1 mg/kg i.p. for 28 days) mitigated the cognitive decline of db/db mice, a transgenic mouse model of T2DM...
April 20, 2018: Neuroscience
Mahmood Haj-Yahya, Hilal A Lashuel
The microtubule-associated protein Tau plays a central role in neurodegeneration and is a leading therapeutic target for the treatment of Alzheimer's disease (AD). Several lines of evidence suggest that post-translational modifications (PTMs) regulate the function(s) of Tau, including its subcellular localization, clearance, aggregation, toxicity, and pathology spreading. However, the lack of tools and methodologies that allow site-specific introduction of PTMs in Tau have limited our ability to dissect the role of PTMs in regulating Tau functions in health and disease...
April 23, 2018: Journal of the American Chemical Society
Pengzhen Wang, Xiaoyao Zheng, Qian Guo, Peng Yang, Xiaoying Pang, Kang Qian, Wei Lu, Qizhi Zhang, Xinguo Jiang
β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is a key enzyme to cleave the amyloid precursor protein to develop Alzheimer's disease (AD). Reducing BACE1 expression in central neuron through RNA interference technology shows great promise to overcome AD. However, to obtain an efficient and neurons-specific delivery of siRNA against BACE1 through systemic administration remains challenging. Here, we design and prepare siRNA nano-carriers based on PEGylated poly(2-(N,N-dimethylamino) ethyl methacrylate) (PEG-PDMAEMA) modified with both the CGN peptide for blood-brain barrier (BBB) penetration and the Tet1 peptide for neuron-specific binding...
April 18, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Yinhui Li, Di Xu, Anyang Sun, See-Lok Ho, Chung-Yan Poon, Hei-Nga Chan, Olivia T W Ng, Ken K L Yung, Hui Yan, Hung-Wing Li, Man Shing Wong
Alzheimer's disease (AD) is the most prevalent but still incurable neurodegenerative form of dementia. Early diagnosis and intervention are crucial for delaying the onset and progression of the disease. We herein report a novel fluoro-substituted cyanine, F-SLOH, which exhibits good Aβ oligomer selectivity with a high binding affinity, attributed to the synergistic effect of strong π-π stacking and intermolecular CH···O and CH···F interactions. The selectivity towards the Aβ oligomers in the brain was ascertained by in vitro labelling on tissue sections and in vivo labelling through the systemic administration of F-SLOH in 7 month APP/PS1 double transgenic (Tg) and APP/PS1/Tau triple Tg mouse models...
December 1, 2017: Chemical Science
Ting-Ting Hou, He-Yun Yang, Wei Wang, Qiao-Qi Wu, Yuan-Ruhua Tian, Jian-Ping Jia
Abnormal amyloid-β (Aβ) aggregates are a striking feature of Alzheimer's disease (AD), and Aβ oligomers have been proven to be crucial in the pathology of AD. Any intervention targeting the generation or aggregation of Aβ can be expected to be useful in AD treatment. Oxidative stress and inflammation are common pathological changes in AD that are involved in the generation and aggregation of Aβ. In the present study, 6-month-old PS1V97L transgenic (Tg) mice were treated with sulforaphane, an antioxidant, for 4 months, and this treatment significantly inhibited the generation and aggregation of Aβ...
2018: Journal of Alzheimer's Disease: JAD
Nicole Cortés, Víctor Andrade, Leonardo Guzmán-Martínez, Matías Estrella, Ricardo B Maccioni
Progressive neurodegenerative pathologies in aged populations are an issue of major concern worldwide. The microtubule-associated protein tau is able to self-aggregate to form abnormal supramolecular structures that include small oligomers up to complex polymers. Tauopathies correspond to a group of diseases that share tau pathology as a common etiological agent. Since microglial cells play a preponderant role in innate immunity and are the main source of proinflammatory factors in the central nervous system (CNS), the alterations in the cross-talks between microglia and neuronal cells are the main focus of studies concerning the origins of tauopathies...
March 23, 2018: International Journal of Molecular Sciences
Qi Gao, Yuqiang Fang, Shiqing Zhang, Hung-Wing Li, Ken K L Yung, King Wai Chiu Lai
Beta amyloid ( ) peptide, which is a common neuropathological hallmark deposit in the brain of patients with Alzheimer's disease, typically comprises 39-43 amino acid residues. peptides exist as isoforms of and with various lengths. In this research, atomic force microscopy (AFM) was applied to investigate aggregations in Hank's Balanced Salt Solution. Toxic effect of oligomer was investigated in live SH-SY5Y neuroblastoma cells by characterizing cell morphology and cell mechanics using high-resolution AFM scanning...
March 2018: IEEE Transactions on Nanobioscience
Norimichi Shirafuji, Tadanori Hamano, Shu-Hui Yen, Nicholas M Kanaan, Hirotaka Yoshida, Kouji Hayashi, Masamichi Ikawa, Osamu Yamamura, Masaru Kuriyama, Yasunari Nakamoto
Increased plasma homocysteinemia is considered a risk factor of dementia, including Alzheimer's disease (AD) and vascular dementia. However, the reason elevated plasma homocysteinemia increases the risk of dementia remains unknown. A pathological hallmark of AD is neurofibrillary tangles (NFTs) that consist of pathologically phosphorylated tau proteins. The effect of homocysteine (Hcy) on tau aggregation was explored using human neuroblastoma M1C cells that constitutively express human wild-type tau (4R0N) under the control of a tetracycline off system, primary mouse cultured neurons, and by inducing hyperhomocysteinemia in a mouse model of tauopathy (HHCy mice)...
March 17, 2018: International Journal of Molecular Sciences
Eleanor Drummond, Fernando Goñi, Shan Liu, Frances Prelli, Henrieta Scholtzova, Thomas Wisniewski
There is growing genetic and proteomic data highlighting the complexity of Alzheimer's disease (AD) pathogenesis. Greater use of unbiased "omics" approaches is being increasingly recognized as essential for the future development of effective AD research, that need to better reflect the multiple distinct pathway abnormalities that can drive AD pathology. The track record of success in AD clinical trials thus far has been very poor. In part, this high failure rate has been related to the premature translation of highly successful results in animal models that mirror only limited aspects of AD pathology to humans...
March 16, 2018: Journal of Alzheimer's Disease: JAD
Balaji Krishnan, Rakez Kayed, Giulio Taglialatela
Introduction: Phospholipase D (PLD), a lipolytic enzyme that breaks down membrane phospholipids, is also involved in signaling mechanisms downstream of seven transmembrane receptors. Abnormally elevated levels of PLD activity are well-established in Alzheimer's disease (AD), implicating the two isoforms of mammalian phosphatidylcholine cleaving PLD (PC-PLD1 and PC-PLD2). Therefore, we took a systematic approach of investigating isoform-specific expression in human synaptosomes and further investigated the possibility of therapeutic intervention using preclinical studies...
2018: Alzheimer's & Dementia: Translational Research & Clinical Interventions
Julia E Gerson, Kathleen M Farmer, Natalie Henson, Diana L Castillo-Carranza, Mariana Carretero Murillo, Urmi Sengupta, Alan Barrett, Rakez Kayed
BACKGROUND: We have evaluated the efficacy of targeting the toxic, oligomeric form of tau protein by passive immunotherapy in a mouse model of synucleinopathy. Parkinson's disease and Lewy body dementia are two of the most common neurodegenerative disorders and are primarily characterized by the accumulation of α-synuclein in Lewy bodies. However, evidence shows that smaller, oligomeric aggregates are likely the most toxic form of the protein. Moreover, a large body of research suggests that α-synuclein interacts with tau in disease and may act in a synergistic mechanism, implicating tau oligomers as a potential therapeutic target...
March 15, 2018: Molecular Neurodegeneration
José A Del Río, Isidre Ferrer, Rosalina Gavín
Several studies have indicated that certain misfolded amyloids composed of tau, β-amyloid or α-synuclein can be transferred from cell to cell, suggesting the contribution of mechanisms reminiscent of those by which infective prions spread through the brain. This process of a 'prion-like' spreading between cells is also relevant as a novel putative therapeutic target that could block the spreading of proteinaceous aggregates throughout the brain which may underlie the progressive nature of neurodegenerative diseases...
March 9, 2018: Progress in Neurobiology
Simona Daniele, Daniela Frosini, Deborah Pietrobono, Lucia Petrozzi, Annalisa Lo Gerfo, Filippo Baldacci, Jonathan Fusi, Chiara Giacomelli, Gabriele Siciliano, Maria Letizia Trincavelli, Ferdinando Franzoni, Roberto Ceravolo, Claudia Martini, Ubaldo Bonuccelli
Neurodegenerative disorders (NDs) are characterized by abnormal accumulation/misfolding of specific proteins, primarily α-synuclein (α-syn), β-amyloid1-42 (Aβ1-42 ) and tau, in both brain and peripheral tissues. In addition to oligomers, the role of the interactions of α-syn with Aβ or tau has gradually emerged. Nevertheless, despite intensive research, NDs have no accepted peripheral markers for biochemical diagnosis. In this respect, Red Blood Cells (RBCs) are emerging as a valid peripheral model for the study of aging-related pathologies...
2018: Frontiers in Molecular Neuroscience
Justyna Sosna, Stephan Philipp, Ricardo Albay, Jorge Mauricio Reyes-Ruiz, David Baglietto-Vargas, Frank M LaFerla, Charles G Glabe
BACKGROUND: Besides the two main classical features of amyloid beta aggregation and tau-containing neurofibrillary tangle deposition, neuroinflammation plays an important yet unclear role in the pathophysiology of Alzheimer's disease (AD). Microglia are believed to be key mediators of neuroinflammation during AD and responsible for the regulation of brain homeostasis by balancing neurotoxicity and neuroprotective events. We have previously reported evidence that neuritic plaques are derived from dead neurons that have accumulated intraneuronal amyloid and further recruit Iba1-positive cells, which play a role in either neuronal demise or neuritic plaque maturation or both...
March 1, 2018: Molecular Neurodegeneration
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