Sunday, July 9, 2017

Scientists uncover the structure of tau filaments from Alzheimer's disease

Scientists uncover the structure of tau filaments from Alzheimer's disease

5 Jul 2017

Researchers at the MRC Laboratory of Molecular Biology (LMB) have, for the first time, revealed the atomic structures of one of the two types of the abnormal filaments which lead to Alzheimer's disease. Understanding the structures of these filaments will be key in developing drugs to prevent their formation.

The researchers, whose study is published today in Nature, believe the structures they have uncovered could also suggest how tau protein may form different filaments in other neurodegenerative diseases.

Alzheimer’s, the most common neurodegenerative disease, is characterised by the existence of two types of abnormal ‘amyloid’ forms of protein which form lesions in the brain. Tau forms filaments inside nerve cells and amyloid-beta forms filaments outside cells. Tau lesions appear to have a stronger correlation to the loss of cognitive ability in patients with the disease.

Almost thirty years ago, scientists at the LMB (including Michel Goedert, one of the senior authors on this paper) identified tau protein as an integral component of the lesions found in Alzheimer’s and a range of other neurodegenerative diseases. But, until now, scientists have been unable to identify the atomic structure of the filaments.

The researchers extracted tau filaments from the brain of a patient who had died with Alzheimer's disease. The filaments were then imaged using cryo-electron microscopy (cryo-EM). Senior author Sjors Scheres and colleagues developed new software in order to calculate the structure of the filaments in sufficient detail to deduce the arrangement of the atoms inside them.

Sjors Scheres said: “It’s very exciting that we were able to use this new technique to visualise filaments from a diseased brain as previous work depended on artificial samples assembled in the laboratory. Amyloid structures can form in many different ways, so it has been unclear how close these lab versions resembled those in human disease.

“Knowing which parts of tau are important for filament formation is relevant for the development of drugs. For example, many pharmaceutical companies are currently using different parts of tau in tests to measure the effect of different drugs on filament formation; this new knowledge should significantly increase the accuracy of such tests."

Fellow senior author Michel Goedert said: “We have known for almost three decades that the abnormal assembly of tau protein into filaments is a defining characteristic of Alzheimer's disease. In 1998, the dysfunction of tau protein was shown to be sufficient for neurodegeneration and dementia. In 2009, the prion-like properties of assembled tau were identified. These properties allow the abnormal form to convert previously normal forms.

“Until now the high-resolution structures of tau or any other disease-causing filaments from human brain tissue have remained unknown. This new work will help to develop better compounds for diagnosing and treating Alzheimer's and other diseases which involve defective tau.”

Dr Rob Buckle, chief science officer at the MRC, which funded the research, said: “This ground-breaking work is a major contribution to our understanding of Alzheimer's disease. Nearly thirty years ago scientists at the LMB were the first to discover that tau protein plays a key role in the disease. Knowing the basic structure of these filaments in diseased tissue is vital for the development of drugs to combat their formation.

“This research opens up new possibilities to study a range of other diseases where the accumulation of abnormal protein filaments plays a role, including Parkinson’s disease, motor neuron disease and prion diseases.”

The work was funded by the MRC, the European Union, US National Institutes of Health and the Department of Pathology and Laboratory Medicine, Indiana University School of Medicine.

Cryo-EM structures of tau filaments from Alzheimer’s disease

Anthony W. P. Fitzpatrick, Benjamin Falcon, Shaoda He, Alexey G. Murzin, Garib Murshudov, Holly J. Garringer, R. Anthony Crowther, Bernardino Ghetti, Michel Goedert & Sjors H. W. Scheres

AffiliationsContributionsCorresponding authors Nature (2017) doi:10.1038/nature23002 Received 24 February 2017 Accepted 05 June 2017 Published online 05 July 2017 Article tools


Abstract• Accession codes• References• Author information• Extended data figures and tables

Alzheimer’s disease is the most common neurodegenerative disease, and there are no mechanism-based therapies. The disease is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in the cerebral cortex. Neurofibrillary lesions comprise paired helical and straight tau filaments, whereas tau filaments with different morphologies characterize other neurodegenerative diseases. No high-resolution structures of tau filaments are available. Here we present cryo-electron microscopy (cryo-EM) maps at 3.4–3.5 Å resolution and corresponding atomic models of paired helical and straight filaments from the brain of an individual with Alzheimer’s disease. Filament cores are made of two identical protofilaments comprising residues 306–378 of tau protein, which adopt a combined cross-β/β-helix structure and define the seed for tau aggregation. Paired helical and straight filaments differ in their inter-protofilament packing, showing that they are ultrastructural polymorphs. These findings demonstrate that cryo-EM allows atomic characterization of amyloid filaments from patient-derived material, and pave the way for investigation of a range of neurodegenerative diseases.

At a glance

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Neurodegeneration: Taming tangled tau

David S. Eisenberg & Michael R. Sawaya Affiliations Corresponding authors Nature (2017) doi:10.1038/nature23094

Published online 05 July 2017

Article tools Citation Rights & permissions Article metrics

The protein tau forms abnormal filamentous aggregates called tangles in the brains of people with neurodegeneration. Structures of two such filaments offer pathways to a deeper understanding of Alzheimer's disease.


P154 Development of an in vitro amplification assay for misfolded proteins in for misfolded proteins in Alzheimer’s diseases (AD) and Parkinson’s disease (PD)

Ms Susana Margarida Silva Correia1
1National Reference Center For Tse, Department Of Neurology, Georg-august University , Göttingen, Germany

A characteristic feature of major neurodegenerative diseases leading to dementia is the progressive accumulation of protein aggregates in the brain in a self-propagation-manner with a regional pattern specific to each disease. The concept of protein misfolding was initially thought to play a crucial role mainly in prion diseases, recent studies identified similar characteristics for amyloid beta, tau and alpha synuclein in various models. The term “prion-like“ protein propagation is now widely used to address the mechanisms which might play a role in amyloidopathies or tauopathies such as Alzheimer’s disease (AD) and alpha synucleinopathies, such as Parkinson’s disease (PD) or Lewy body dementia (LBD).

We established the RT-QuIC for the amplification of prion protein scrapie (PrPSc) in human brain tissue and cerebrospinal fluid (CSF) of CJD-patients (Schmitz M et al, 2016). The technique bears a huge diagnostic and analytical potential also for other misfolded proteins, which are showing a prion-like mechanism of protein misfolding.

The aim of the study is the implementation of the amyloid beta and alpha synuclein QuIC in diagnostic of neurodegenerative diseases. In particular, we aim to improve the diagnostic of AD, PD and LBD. The implementation of the amyloid beta and alpha synuclein QuIC in human disease diagnostic requires the analysis of a huge cohort of patients (available from our biobank) consisting of healthy controls, patients with alternative diagnosis as well as of patients with AD and PD.

The aim of the study is to develop the RT-QuIC to create a novel diagnostic-tests for other neurodegenerative diseases such as AD and PD. In a first step, we plan to produce recombinant amyloid beta and alpha synuclein and to test systematically different substrates in our QuIC-amplification assay. After validation of the most suitable substrates, we will applicate the RT-QuIC for the detection of amyloid beta and alpha synuclein aggregates in CSF from AD- and PD-patients.


P188 Misfolded PrP is not always associated with formation of p-tau

Dr Debbie Brown1, Mr Declan King1, Dr Rona Barron1, Professor Pedro Piccardo1
1Roslin Institute, Edinburgh, United Kingdom

The conversion of cellular prion protein into a misfolded isoform is central to the development of prion diseases. Amyloid beta (Aβ) and hyperphosphorylated tau (p-tau) participate in the pathogenesis of Alzheimer´s disease (AD). Additionally several prion diseases in humans accumulate p-tau in the brain and therefore we hypothesise that proteins that participate in the pathogenesis of one disease may play a role in other disorders to establish complex proteinopathies, a mechanism that could explain the phenotypic variability observed in prion diseases. To explore this possibility we analysed p-tau accumulation in mouse models with varying degrees of PrP deposits in the brain. We used animals inoculated with :- mouse-adapted prion agents, typical and atypical bovine spongiform encephalopathy agents along with mice inoculated with wild-type (Wt) /mutant (101L) recombinant PrP fibrils and mice overexpressing 101L PrP. We observed that p-tau is consistently present in animals with prion infectivity (i.e. models that transmit disease upon serial passage). However, p-tau is not observed in non-prion mice inoculated with recombinant PrP fibrils or mice overexpressing PrP, both of which form large amyloid plaques in the absence of disease. The data suggest that p-tau is not necessarily associated with deposition of misfolded PrP, but that the interaction between the prion agent and host regulates the formation of p-tau and may contribute to the heterogeneous phenotype of prion diseases.


P17 Induction of transmissible tau pathology by traumatic brain Injury

Dr Elisa R Zanier1, Ilaria Bertani1, Dr Maria Antonietta Chiaravalloti1, Dr Eliana Sammali1, Dr Francesca Pischiutta1, Dr Gloria Vegliante1, Dr Fabrizio Ortolano2, Dr Nino Stocchetti2,3, Dr Maria-Grazia De Simoni1, Dr Roberto Chiesa1
1Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy, 2Università degli Studi di Milano, Milano, Italy, 3Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico di Milano, Milano, Italy

Aims: The aim of this study was to test whether traumatic brain injury (TBI), a risk factor for Alzheimer’s disease and chronic traumatic encephalopathy, induces a tau pathology that spreads in the brain in a prion-like manner, causing functional and histopathological abnormalities.

Methods: C57BL/6J mice were subjected to focal TBI by single controlled cortical impact, and the presence of pathological tau was investigated by immunohistochemistry and Western blot using antibodies specific for different phosphorylated tau isoforms. The emergence of self-propagating tau isoform was investigated by inoculating 10% brain homogenates from TBI mice and humans into the brain of naïve C57BL/6J mice.

Results: Hyperphosphorylated tau was detected in the injured brain hemisphere at 3 months post-TBI, and in the ipsi and contralateral hemispheres at 12 months, indicating progressive spreading of tauopathy. Mice inoculated with TBI brain homogenates developed memory deficits detectable by the novel object recognition task at 4, 8 and 12 months after inoculation. Immunohistochemistry at 12 months post-inoculation showed hyperphosphorylated tau in the injected area and remote brain regions.

Conclusions: Results establish that a single focal TBI induces a tau pathology in wild-type mice that progressively spreads from the site of injury to other brain regions. They also show the emergence of self-propagating tau isoforms in the brains of TBI mice and humans, which can be transmitted to wild-type mice like bona fide prions, inducing memory dysfunction. These data suggest that inhibiting propagation of tau may become a treatment strategy in TBI.

=====WOW AMAZING...TSS=====


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PRION 2017 P115 α- Synuclein prions from MSA patients exhibit similar transmission properties as PrPSc prions

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Prion 2017 Conference Transmissible prions in the skin of Creutzfeldt-Jakob disease patients


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Thursday, June 29, 2017


Wednesday, May 24, 2017

PRION2017 CONFERENCE VIDEO UPDATE 23 – 26 May 2017 Edinburgh UPDATE 1

Subject: PRION2017 CONFERENCE VIDEO UPDATE 23 – 26 May 2017 Edinburgh

*see archives of previous Prion Conferences, the ones that are still available, scroll down towards bottom in this link.


National Prion Disease Pathology Surveillance Center Cases Examined(1) (May 18, 2017)

Terry S. Singeltary Sr.

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