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alzheimer's disease prion diseases

Grant Norman, Jody Campeau, Valerie L Sim
Prion diseases are a group of neurodegenerative diseases associated with the misfolding of the cellular prion protein (PrPC ) into the infectious form (PrPSc ). There are currently no treatments for prion disease. Bile acids have the ability to protect hepatocytes from apoptosis and are neuroprotective in animal models of other protein folding neurodegenerative diseases including Huntington's, Parkinson's, and Alzheimer's disease. Importantly, bile acids are approved for clinical use in patients with cirrhosis, and have recently been shown to be safe and possibly effective in pilot trials of patients with amyotrophic lateral sclerosis (ALS)...
May 21, 2018: Antimicrobial Agents and Chemotherapy
Neng-Wei Hu, Grant T Corbett, Steven Moore, Igor Klyubin, Tiernan T O'Malley, Dominic M Walsh, Frederick J Livesey, Michael J Rowan
The early stages of Alzheimer's disease are associated with synaptic dysfunction prior to overt loss of neurons. To identify extracellular molecules that impair synaptic plasticity in the brain, we studied the secretomes of human iPSC-derived neuronal models of Alzheimer's disease. When introduced into the rat brain, secretomes from human neurons with either a presenilin-1 mutation, amyloid precursor protein duplication, or trisomy of chromosome 21 all strongly inhibit hippocampal long-term potentiation. Synaptic dysfunction caused by presenilin-1 mutant and amyloid precusor protein duplication secretomes is mediated by Aβ peptides, whereas trisomy of chromosome 21 (trisomy 21) neuronal secretomes induce dysfunction through extracellular tau...
May 15, 2018: Cell Reports
Sarah K Kaufman, Kelly Del Tredici, Talitha L Thomas, Heiko Braak, Marc I Diamond
Alzheimer's disease (AD) is characterized by accumulation of tau neurofibrillary tangles (NFTs) and, according to the prion model, transcellular propagation of pathological "seeds" may underlie its progression. Staging of NFT pathology with phospho-tau antibody is useful to classify AD and primary age-related tauopathy (PART) cases. The locus coeruleus (LC) shows the earliest phospho-tau signal, whereas other studies suggest that pathology begins in the transentorhinal/entorhinal cortices (TRE/EC)...
May 11, 2018: Acta Neuropathologica
Heather H C Lau, Angus Lau, Joel C Watts
Prions and other self-propagating protein aggregates can exist as distinct strains, which are thought to represent different conformations of aggregates. There is growing evidence that protein aggregate strains may be important for understanding the biology of common neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. While methodology for discriminating prion strains is in widespread use, there is a paucity of tools for comparing the conformational properties of aggregates composed of β-amyloid (Aβ) peptide or α-synuclein protein, particularly when present in complex samples such as brain extracts...
2018: Methods in Molecular Biology
Sarah L DeVos, Bianca T Corjuc, Derek H Oakley, Chloe K Nobuhara, Riley N Bannon, Alison Chase, Caitlin Commins, Jose A Gonzalez, Patrick M Dooley, Matthew P Frosch, Bradley T Hyman
Alzheimer's disease (AD) is defined by the presence of intraneuronal neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau aggregates as well as extracellular amyloid-beta plaques. The presence and spread of tau pathology through the brain is classified by Braak stages and thought to correlate with the progression of AD. Several in vitro and in vivo studies have examined the ability of tau pathology to move from one neuron to the next, suggesting a "prion-like" spread of tau aggregates may be an underlying cause of Braak tau staging in AD...
2018: Frontiers in Neuroscience
Hai-Ying Zhang, Yi-Heng Liu, Yuan Fu, Peng-Cheng Chen, Rui Lu, Jian-Xing Li, Ming-Hui Chen, Hao-Chi Yang, Yu-Sheng Zhang
OBJECTIVE: To study the effects of intrahippocampal injection of cellular prion protein (PrPC ) antibody on cognitive deficits of APPswe/PSEN1dE9 transgenic mice. METHODS: Eight-month-old male APPswe/PSEN1dE9 transgenic mice were subjected to bilateral intrahippocampal injection of a single dose (2 µL) of anti-PrPC monoclonal antibody (EP1802Y) or PBS, with wild-type C57Bl/6J mice serving as the control group. After two months, the mice were tested for cognitive behaviors using open filed (OF) test, Morris water maze (MWM) test, fear conditioning (FC) test, and novel object recognition (NOR) test, and immunohistochemistry was used to examine the changes in hippocampal expression of Aβ1-42 ...
April 20, 2018: Nan Fang Yi Ke da Xue Xue Bao, Journal of Southern Medical University
José Miguel Flores-Fernández, Vineet Rathod, Holger Wille
Pathogenic amyloids are the main feature of several neurodegenerative disorders, such as Creutzfeldt⁻Jakob disease, Alzheimer’s disease, and Parkinson’s disease. High resolution structures of tau paired helical filaments (PHFs), amyloid-β(1-42) (Aβ(1-42)) fibrils, and α-synuclein fibrils were recently reported using cryo-electron microscopy. A high-resolution structure for the infectious prion protein, PrPSc , is not yet available due to its insolubility and its propensity to aggregate, but cryo-electron microscopy, X-ray fiber diffraction, and other approaches have defined the overall architecture of PrPSc as a 4-rung β-solenoid...
May 4, 2018: Pathogens
Jieling Qin, Dong Gyu Jo, Misuk Cho, Youngkwan Lee
Amyloid-beta oligomers (AβΟ) are considered to be reliable biomarkers for the diagnosis of Alzheimer' disease (AD), and the cellular prion protein (PrPC ) is identified as a receptor for AβO. We demonstrated a label and antibody-free electrochemical biosensor for the selective detection of AβO using an electrically conductive poly(pyrrole-2-carboxylic acid) (PPyCOOH) linking agent and PrPC receptor. In the fabrication of the biosensor, each step was characterized by electrochemical impedance spectroscopy and cyclic voltammetry...
May 1, 2018: Biosensors & Bioelectronics
Auriane Maïza, Sandrine Chantepie, Cecilia Vera, Alexandre Fifre, Min Bao Huynh, Olivier Stettler, Mohand Ouidir Ouidja, Dulce Papy-Garcia
Neurodegenerative disorders, such as Alzheimer's, Parkinson's, and prion diseases, are directly linked to the formation and accumulation of protein aggregates in the brain. These aggregates, principally made of proteins or peptides that clamp together after acquisition of β-folded structures, also contain heparan sulfates. Several lines of evidence suggest that heparan sulfates centrally participate in the protein aggregation process. In vitro, they trigger misfolding, oligomerisation, and fibrillation of amyloidogenic proteins, such as Aβ, tau, α-synuclein, prion protein, etc...
May 4, 2018: FEBS Letters
Samir Abu-Rumeileh, Sabina Capellari, Piero Parchi
Rapidly progressive Alzheimer's disease (rpAD) has recently been recognized as a clinical disease subtype characterized by rapidly progressive cognitive decline and/or short disease duration, and the possible occurrence of early focal neurological signs. Consistently, rpAD represents a relatively frequent alternative diagnosis among cases referred as possible or probable Creutzfeldt-Jakob disease (CJD) to surveillance centers for prion disease worldwide. Indeed, the early clinical differential diagnosis between the two disorders can be challenging given the partial overlap in clinical features and cerebrospinal fluid (CSF) levels of the protein surrogate markers 14-3-3 and total-tau...
April 25, 2018: Journal of Alzheimer's Disease: JAD
Ajay Ashok, Neena Singh
The prion protein (PrPC ), a mainly neuronal protein, is known to modulate glucose homeostasis in mouse models. We explored the underlying mechanism in mouse models and the human pancreatic β-cell line 1.1B4. We report expression of PrPC on mouse pancreatic β-cells, where it promoted uptake of iron through divalent-metal-transporters. Accordingly, pancreatic iron stores in PrP knockout mice (PrP-/- ) were significantly lower than wild type (PrP+/+ ) controls. Silencing of PrPC in 1.1B4 cells resulted in significant depletion of intracellular (IC) iron, and remarkably, upregulation of glucose transporter GLUT2 and insulin...
April 26, 2018: Scientific Reports
N Siva Subramaniam, C S Bawden, H Waldvogel, R M L Faull, G S Howarth, R G Snell
Neurodegenerative diseases (NDDs) are incapacitating disorders that result in progressive motor and cognitive impairment. These disease include Alzheimer's disease the most common cause of dementia, frontotemporal dementia, amyotrophic lateral sclerosis, dementia with Lewy bodies, Parkinson's, Huntington's, Friedreich's ataxia, and prion disease. Dementia causing NDDs impose a high social and economic burden on communities around the world. Rapid growth in knowledge regarding the pathogenic mechanisms and disease-associated biomarkers of these diseases in the past few decades have accelerated the development of new diagnostic methods and therapeutic opportunities...
April 20, 2018: Brain Research
Giuseppe Legname, Tommaso Virgilio, Edoardo Bistaffa, Chiara Maria Giulia De Luca, Marcella Catania, Paola Zago, Elisa Isopi, Ilaria Campagnani, Fabrizio Tagliavini, Giorgio Giaccone, Fabio Moda
Pin1 is a peptidyl-prolyl isomerase that induces the cis-trans conversion of specific Ser/Thr-Pro peptide bonds in phosphorylated proteins, leading to conformational changes through which Pin1 regulates protein stability and activity. Since down-regulation of Pin1 has been described in several neurodegenerative disorders, including Alzheimer's Disease (AD), Parkinson's Disease (PD) and Huntington's Disease (HD), we investigated its potential role in prion diseases. Animals generated on wild-type (Pin1+/+ ), hemizygous (Pin1+/- ) or knock-out (Pin1-/- ) background for Pin1 were experimentally infected with RML prions...
April 20, 2018: Prion
Qi Shi, Jian-Le Li, Yue Ma, Li-Ping Gao, Kang Xiao, Jing Wang, Wei Zhou, Cao Chen, Yan-Jun Guo, Xiao-Ping Dong
The levels of ryanodine receptors (RyRs) are usually increased in the brains of human Alzheimer disease (AD) and AD animal models. To evaluate the underlying alteration of brain RyRs in prion disease, scrapie infected cell line SMB-S15 and its infected mice were tested. RyR2 specific Western blots revealed markedly decreased RyR2 levels both in the cells and in the brains of infected mice. Assays of the brain samples of other scrapie (agents 139A and ME7) infected mice collected at different time-points during incubation period showed time-dependent decreases of RyR2...
April 20, 2018: Prion
V Cubinkova, B Valachova, I Uhrinova, V Brezovakova, T Smolek, S Jadhav, N Zilka
Alzheimer's disease represents the most common form of dementia and belongs to the group of neurodegenerative disorders characterized by progressive loss of neurons in the central nervous system. In the pathogenesis of Alzheimer's disease several etiologic and pathogenic factors exist, which lead to the dysfunction of neurotransmitter systems and consequent cognitive decline. Last three decades have delivered a crucial progress leading to better understanding of Alzheimer's disease, however, the exact mechanisms of pathology remain unclear...
2018: Bratislavské Lekárske Listy
Ryo Honda
Transmissible spongiform encephalopathy (TSE) is associated with misfolding of prion protein (PrP) into an amyloid β-rich aggregate. Previous studies have indicated that PrP interacts with Alzheimer disease amyloid-β peptide (Aβ), but it remains elusive how this interaction impacts on the misfolding of PrP. This study presents the first in vitro evidence that Aβ induces PrP-amyloid formation at submicromolar concentrations. Interestingly, systematic mutagenesis of PrP revealed that Aβ requires no specific amino acid sequences in PrP, and induces the misfolding of other unrelated proteins (insulin and lysozyme) into amyloid fibrils in a manner analogous to PrP...
April 12, 2018: Angewandte Chemie
Alejandro Ruiz-Riquelme, Heather H C Lau, Erica Stuart, Adrienn N Goczi, Zhilan Wang, Gerold Schmitt-Ulms, Joel C Watts
The amyloid cascade hypothesis posits that the initiating event in Alzheimer's disease (AD) is the aggregation and deposition of the β-amyloid (Aβ) peptide, which is a proteolytic cleavage product of the amyloid precursor protein (APP). Mounting evidence suggests that the formation and spread of prion-like Aβ aggregates during AD may contribute to disease progression. Inoculation of transgenic mice that overexpress APP with pre-formed Aβ aggregates results in the prion-like induction of cerebral Aβ deposition...
April 3, 2018: Acta Neuropathologica Communications
Hanna Nieznanska, Magdalena Bandyszewska, Krystyna Surewicz, Tomasz Zajkowski, Witold K Surewicz, Krzysztof Nieznanski
Soluble form of the prion protein (PrP) has been previously shown to interact with amyloid-β (Aβ) peptides, suppressing their fibrillization as well as toxicity, which indicates that this protein may play a protective role in Alzheimer's disease (AD). The shortest known PrP fragment retaining all of these properties corresponds to physiologically generated proteolytic polypeptide PrP23-110/111, called N1. Here we have identified two N1-derived synthetic peptides, encompassing residues 23-50 (PrP23-50) and 90-112 (PrP90-112), which bind to Aβ1-42 protofibrillar oligomers as well as amyloid fibrils...
March 28, 2018: Biochimica et Biophysica Acta
Meenakshi Verma, Amandeep Girdhar, Basant Patel, Nirmal K Ganguly, Ritushree Kukreti, Vibha Taneja
Interactions amongst different amyloid proteins have been proposed as a probable mechanism of aggregation and thus an important risk factor for the onset as well as progression of various neurodegenerative disorders including Alzheimer's, Parkinson's, Huntington's, and Amyotrophic Lateral Sclerosis. Evidences suggest that transthyretin (TTR), a plasma protein associated with transthyretin amyloidosis or familial polyneuropathy (FAP) interacts with heterologous amyloid proteins including amyloid beta and islet amyloid polypeptide...
2018: Frontiers in Molecular Neuroscience
Franziska Kundel, Liu Hong, Benjamin Falcon, William McEwan, Thomas C T Michaels, Georg Meisl, Noemi Esteras, Andrey Y Abramov, Tuomas P J Knowles, Michel Goedert, David Klenerman
The ordered assembly of amyloidogenic proteins causes a wide spectrum of common neurodegenerative diseases, including Alzheimer's and Parkinson's disease. These diseases share common features with prion diseases, in which misfolded protein can self-replicate and transmit disease across different hosts. Deciphering the molecular mechanisms that underlie the amplification of aggregates is fundamental to understand how pathological deposits can spread through the brain and drive disease. Here, we used single-molecule microscopy to study the assembly and replication of tau at the single aggregate level...
March 28, 2018: ACS Chemical Neuroscience
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