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Tau oligomers

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
Diana L Castillo-Carranza, Marcos J Guerrero-Muñoz, Urmi Sengupta, Julia E Gerson, Rakez Kayed
BACKGROUND: The coexistence of α-synuclein and tau aggregates in several neurodegenerative disorders, including Parkinson's disease and Alzheimer's disease, raises the possibility that a seeding mechanism is involved in disease progression. METHODS: To further investigate the role of α-synuclein in the tau aggregation pathway, we performed a set of experiments using both recombinant and brain-derived tau and α-synuclein oligomers to seed monomeric tau aggregation in vitro and in vivo...
January 17, 2018: Biological Psychiatry
Yan Zhou, Jianhua Shi, Dandan Chu, Wen Hu, Zongyu Guan, Cheng-Xin Gong, Khalid Iqbal, Fei Liu
Microtubule (MT) associated protein tau is abnormally hyperphosphorylated and aggregated into paired helical filaments (PHFs), which manifest as neurofibrillary tangles (NFTs) in the brains of individuals with Alzheimer's disease (AD) and related tauopathies. Hyperphosphorylation and truncation of tau have been linked to the progression of the disease. However, the nature of phosphorylation and truncation of tau in AD brain are not very clear. In the present study we investigated the association of phosphorylation and truncation with high-molecular weight oligomers of tau (HMW-tau) in post-mortem AD brain by western blots...
2018: Frontiers in Aging Neuroscience
Simona Daniele, Deborah Pietrobono, Jonathan Fusi, Annalisa Lo Gerfo, Eugenio Cerri, Lucia Chico, Caterina Iofrida, Lucia Petrozzi, Filippo Baldacci, Chiara Giacomelli, Fabio Galetta, Gabriele Siciliano, Ubaldo Bonuccelli, Maria L Trincavelli, Ferdinando Franzoni, Claudia Martini
The loss of protein homeostasis that has been associated with aging leads to altered levels and conformational instability of proteins, which tend to form toxic aggregates. In particular, brain aging presents characteristic patterns of misfolded oligomers, primarily constituted of β-amyloid (Aβ), tau, and α-synuclein (α-syn), which can accumulate in neuronal membranes or extracellular compartments. Such aging-related proteins can also reach peripheral compartments, thus suggesting the possibility to monitor their accumulation in more accessible fluids...
2018: Frontiers in Aging Neuroscience
Andre F Batista, Leticia Forny-Germano, Julia R Clarke, Natalia M Lyra E Silva, Jordano Brito-Moreira, Susan E Boehnke, Andrew Winterborn, Brian C Coe, Ann Lablans, Juliana F Vital, Suelen A Marques, Ana M B Martinez, Matthias Gralle, Christian Holscher, William L Klein, Jean-Christophe Houzel, Sergio T Ferreira, Douglas P Munoz, Fernanda G De Felice
Alzheimer's disease (AD) is a devastating neurological disorder that still lacks an effective treatment, and this has stimulated an intense pursuit of disease-modifying therapeutics. Given the increasingly recognized link between AD and defective brain insulin signaling, we investigated the actions of liraglutide, a glucagon-like peptide-1 (GLP-1) analog marketed for treatment of type 2 diabetes, in experimental models of AD. Insulin receptor pathology is an important feature of AD brains that impairs the neuroprotective actions of central insulin signaling...
February 12, 2018: Journal of Pathology
Tomas T Olsson, Oxana Klementieva, Gunnar K Gouras
Alzheimer's disease (AD) brain tissue can act as a seed to accelerate aggregation of amyloid-β (Aβ) into plaques in AD transgenic mice. Aβ seeds have been hypothesized to accelerate plaque formation in a prion-like manner of templated seeding and intercellular propagation. However, the structure(s) and location(s) of the Aβ seeds remain unknown. Moreover, in contrast to tau and α-synuclein, an in vitro system with prion-like Aβ has not been reported. Here we treat human APP expressing N2a cells with AD transgenic mouse brain extracts to induce inclusions of Aβ in a subset of cells...
January 29, 2018: Neurobiology of Disease
A Harrison Brody, Stephen M Strittmatter
Alzheimer's disease (AD) represents an impending global health crisis, yet the complexity of AD pathophysiology has so far precluded the development of any interventions to successfully slow or halt AD progression. It is clear that accumulation of Amyloid-beta (Aβ) peptide triggers progressive synapse loss to cause AD symptoms. Once initiated by Aβ, disease progression is complicated and accelerated by inflammation and by tau pathology. The recognition that Aβ peptide assumes multiple distinct states and that soluble oligomeric species (Aβo) are critical for synaptic damage is central to molecular understanding of AD...
2018: Advances in Pharmacology
Fernando Goñi, Mitchell Martá-Ariza, Krystal Herline, Daniel Peyser, Allal Boutajangout, Pankaj Mehta, Eleanor Drummond, Frances Prelli, Thomas Wisniewski
BACKGROUND: Oligomeric forms of amyloid-β (Aβ) and tau are increasing being recognized as key toxins in the pathogenesis of Alzheimer's disease (AD). METHODS: We developed a novel monoclonal antibody (mAb), GW-23B7, that recognizes β-sheet secondary structure on pathological oligomers of neurodegenerative diseases. RESULTS: The pentameric immunoglobulin M kappa chain (IgMκp) we developed specifically distinguishes intra- and extracellular pathology in human AD brains...
January 29, 2018: Alzheimer's Research & Therapy
Filippa Lo Cascio, Rakez Kayed
Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder affecting millions of people worldwide. Therefore, finding effective interventions and therapies is extremely important. AD is one of over 20 different disorders known as tauopathies, characterized by the pathological aggregation and accumulation of tau, a microtubule-associated protein. Tau aggregates are heterogeneous and can be divided into two major groups: large meta-stable fibrils, including neurofibrillary tangles, and oligomers...
January 29, 2018: ACS Chemical Neuroscience
Chelsea T Tiernan, Elliott J Mufson, Nicholas M Kanaan, Scott E Counts
Although tau is the primary constituent of neurofibrillary tangles (NFTs), evidence suggests that its toxic moiety is oligomeric in Alzheimer disease (AD). In this regard, tau oligomers correlate more strongly with neuronal loss than NFTs and exhibit neurotoxicity in preclinical AD models. Here, we investigated the spatiotemporal progression of oligomeric tau accumulation within the highly vulnerable cholinergic neurons of the nucleus basalis of Meynert (nbM) in AD. Tissue from subjects who died with a clinical diagnosis of no cognitive impairment, mild cognitive impairment, or AD was immunostained with the tau oligomeric complex 1 (TOC1) antibody, a marker of tau oligomers, and p75NTR, a cholinergic cell marker...
January 25, 2018: Journal of Neuropathology and Experimental Neurology
V Guru KrishnaKumar, Ashim Paul, Ehud Gazit, Daniel Segal
Intra-cellular tau protein tangles and extra-cellular β-amyloid plaques are hallmarks of Alzheimer's disease (AD), characterized by the conversion of natively unfolded monomeric protein/peptide into misfolded β-sheet rich aggregates. Therefore, inhibiting the aggregation cascade or disassembling the pre-formed aggregates becomes a pivotal event in disease treatment. In the present study, we show that Naphthoquinone-Tryptophan hybrids, i.e., NQTrp and Cl-NQTrp significantly disrupted the pre-formed fibrillar aggregates of Tau-derived PHF6 (VQIVYK) peptide and full-length tau protein in vitro, in a dose-dependent manner as evident from ThS assay, CD spectroscopy, and TEM...
January 8, 2018: Scientific Reports
Franziska Kundel, Suman De, Patrick Flagmeier, Mathew H Horrocks, Magnus Kjaergaard, Sarah L Shammas, Sophie E Jackson, Christopher M Dobson, David Klenerman
As a key player of the protein quality control network of the cell, the molecular chaperone Hsp70 inhibits the aggregation of the amyloid protein tau. To date, the mechanism of this inhibition and the tau species targeted by Hsp70 remain unknown. This is partly due to the inherent difficulty of studying amyloid aggregates because of their heterogeneous and transient nature. Here, we used ensemble and single-molecule fluorescence measurements to dissect how Hsp70 counteracts the self-assembly process of K18 tau with the pathological deletion ∆K280...
January 4, 2018: ACS Chemical Biology
Brandon Lucke-Wold, Kay Seidel, Rub Udo, Bennet Omalu, Mark Ornstein, Richard Nolan, Charles Rosen, Joel Ross
Progressive neurodegenerative diseases plague millions of individuals both in the United States and across the world. The current pathology of progressive neurodegenerative tauopathies, such as Alzheimer's disease (AD), Pick's disease, frontotemporal dementia (FTD), and progressive supranuclear palsy, primarily revolves around phosphorylation and hyperphosphorylation of the tau protein. However, more recent evidence suggests acetylation of tau protein at lysine 280 may be a critical step in molecular pathology of these neurodegenerative diseases prior to the tau hyperphosphorylation...
2017: Journal of Neurology and Neurosurgery
Daniel J Apicco, Peter E A Ash, Brandon Maziuk, Chelsey LeBlang, Maria Medalla, Ali Al Abdullatif, Antonio Ferragud, Emily Botelho, Heather I Ballance, Uma Dhawan, Samantha Boudeau, Anna Lourdes Cruz, Daniel Kashy, Aria Wong, Lisa R Goldberg, Neema Yazdani, Cheng Zhang, Choong Y Ung, Yorghos Tripodis, Nicholas M Kanaan, Tsuneya Ikezu, Pietro Cottone, John Leszyk, Hu Li, Jennifer Luebke, Camron D Bryant, Benjamin Wolozin
Emerging studies suggest a role for tau in regulating the biology of RNA binding proteins (RBPs). We now show that reducing the RBP T-cell intracellular antigen 1 (TIA1) in vivo protects against neurodegeneration and prolongs survival in transgenic P301S Tau mice. Biochemical fractionation shows co-enrichment and co-localization of tau oligomers and RBPs in transgenic P301S Tau mice. Reducing TIA1 decreased the number and size of granules co-localizing with stress granule markers. Decreasing TIA1 also inhibited the accumulation of tau oligomers at the expense of increasing neurofibrillary tangles...
January 2018: Nature Neuroscience
Min Jeong Wang, SangHak Yi, Jee-Young Han, So Young Park, Jae-Won Jang, In Kook Chun, Sang Eun Kim, Byoung Sub Lee, Gwang Je Kim, Ji Sun Yu, Kuntaek Lim, Sung Min Kang, Young Ho Park, Young Chul Youn, Seong Soo A An, SangYun Kim
BACKGROUND: Soluble amyloid-β (Aβ) oligomers are the major toxic substances associated with the pathology of Alzheimer's disease (AD). The ability to measure Aβ oligomer levels in the blood would provide simple and minimally invasive tools for AD diagnostics. In the present study, the recently developed Multimer Detection System (MDS) for AD, a new enzyme-linked immunosorbent assay for measuring Aβ oligomers selectively, was used to detect Aβ oligomers in the plasma of patients with AD and healthy control individuals...
December 15, 2017: Alzheimer's Research & Therapy
Cheril Tapia-Rojas, Nibaldo C Inestrosa
Alzheimer's disease (AD) is a neurodegenerative pathology characterized by aggregates of amyloid-β (Aβ) and phosphorylated tau protein, synaptic dysfunction, and spatial memory impairment. The Wnt signaling pathway has several key functions in the adult brain and has been associated with AD, mainly as a neuroprotective factor against Aβ toxicity and tau phosphorylation. However, dysfunction of Wnt/β-catenin signaling might also play a role in the onset and development of the disease. J20 APPswInd transgenic (Tg) mouse model of AD was treated i...
December 14, 2017: Journal of Neurochemistry
Tarek Mohamed, Sarbjeet Singh Gujral, Praveen P N Rao
We studied the interactions of a tau derived hexapeptide AcPHF6 with beta-amyloid peptides Aβ40 and Aβ42 which reveals its unusual ability to promote Aβ fibrillogenesis. The results demonstrate that the N-acetylated and C-amidated AcPHF6 hexapeptide can cause significant acceleration in Aβ40 and Aβ42 fibril growth. Aggregation kinetic studies at pH 7.4 show that at 25 μM, AcPHF6 hexapeptide was able to cause ~2.3-fold increase in Aβ40 fibrillogenesis dramatically changing the aggregation kinetics. In addition, AcPHF6 peptide was able to reduce cellular toxicity mediated by Aβ40 and Aβ42 in hippocampal neuronal cell line (HT22)...
December 14, 2017: ACS Chemical Neuroscience
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