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  1. Article ; Online: Disease-Associated Mutations in Tau Encode for Changes in Aggregate Structure Conformation.

    Sun, Kerry T / Patel, Tark / Kang, Sang-Gyun / Yarahmady, Allan / Srinivasan, Mahalashmi / Julien, Olivier / Heras, Jónathan / Mok, Sue-Ann

    ACS chemical neuroscience

    2023  Volume 14, Issue 24, Page(s) 4282–4297

    Abstract: The accumulation of tau fibrils is associated with neurodegenerative diseases, which are collectively termed tauopathies. Cryo-EM studies have shown that the packed fibril core of tau adopts distinct structures in different tauopathies, such as Alzheimer' ...

    Abstract The accumulation of tau fibrils is associated with neurodegenerative diseases, which are collectively termed tauopathies. Cryo-EM studies have shown that the packed fibril core of tau adopts distinct structures in different tauopathies, such as Alzheimer's disease, corticobasal degeneration, and progressive supranuclear palsy. A subset of tauopathies are linked to missense mutations in the tau protein, but it is not clear whether these mutations impact the structure of tau fibrils. To answer this question, we developed a high-throughput protein purification platform and purified a panel of 37 tau variants using the full-length 0N4R splice isoform. Each of these variants was used to create fibrils
    MeSH term(s) Humans ; tau Proteins/metabolism ; Tauopathies/metabolism ; Alzheimer Disease/metabolism ; Mutation/genetics
    Chemical Substances tau Proteins
    Language English
    Publishing date 2023-12-06
    Publishing country United States
    Document type Journal Article
    ISSN 1948-7193
    ISSN (online) 1948-7193
    DOI 10.1021/acschemneuro.3c00422
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Native PLGA nanoparticles attenuate Aβ-seed induced tau aggregation under in vitro conditions: potential implication in Alzheimer's disease pathology.

    Paul, Pallabi Sil / Patel, Tark / Cho, Jae-Young / Yarahmady, Allan / Khalili, Aria / Semenchenko, Valentyna / Wille, Holger / Kulka, Marianna / Mok, Sue-Ann / Kar, Satyabrata

    Scientific reports

    2024  Volume 14, Issue 1, Page(s) 144

    Abstract: Evidence suggests that beta-amyloid (Aβ)-induced phosphorylation/aggregation of tau protein plays a critical role in the degeneration of neurons and development of Alzheimer's disease (AD), the most common cause of dementia affecting the elderly ... ...

    Abstract Evidence suggests that beta-amyloid (Aβ)-induced phosphorylation/aggregation of tau protein plays a critical role in the degeneration of neurons and development of Alzheimer's disease (AD), the most common cause of dementia affecting the elderly population. Many studies have pursued a variety of small molecules, including nanoparticles conjugated with drugs to interfere with Aβ and/or tau aggregation/toxicity as an effective strategy for AD treatment. We reported earlier that FDA approved PLGA nanoparticles without any drug can attenuate Aβ aggregation/toxicity in cellular/animal models of AD. In this study, we evaluated the effects of native PLGA on Aβ seed-induced aggregation of tau protein using a variety of biophysical, structural and spectroscopic approaches. Our results show that Aβ
    MeSH term(s) Aged ; Animals ; Humans ; Alzheimer Disease/metabolism ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Phosphorylation ; Nanoparticles
    Chemical Substances tau Proteins ; Amyloid beta-Peptides
    Language English
    Publishing date 2024-01-02
    Publishing country England
    Document type Journal Article
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-023-50465-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Alzheimer's disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model.

    Carling, Gillian K / Fan, Li / Foxe, Nessa R / Norman, Kendra / Ye, Pearly / Wong, Man Ying / Zhu, Daphne / Yu, Fangmin / Xu, Jielin / Yarahmady, Allan / Chen, Hao / Huang, Yige / Amin, Sadaf / Zacharioudakis, Emmanouil / Chen, Xiaoying / Holtzman, David M / Mok, Sue-Ann / Gavathiotis, Evripidis / Sinha, Subhash C /
    Cheng, Feixiong / Luo, Wenjie / Gong, Shiaoching / Gan, Li

    bioRxiv : the preprint server for biology

    2024  

    Abstract: The strongest risk factors for Alzheimer's disease (AD) include the χ4 allele of apolipoprotein E (APOE), ... ...

    Abstract The strongest risk factors for Alzheimer's disease (AD) include the χ4 allele of apolipoprotein E (APOE), the
    Language English
    Publishing date 2024-01-25
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.01.24.577107
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Human iPSC 4R tauopathy model uncovers modifiers of tau propagation.

    Parra Bravo, Celeste / Giani, Alice Maria / Madero-Perez, Jesus / Zhao, Zeping / Wan, Yuansong / Samelson, Avi J / Wong, Man Ying / Evangelisti, Alessandro / Cordes, Ethan / Fan, Li / Ye, Pearly / Zhu, Daphne / Pozner, Tatyana / Mercedes, Maria / Patel, Tark / Yarahmady, Allan / Carling, Gillian K / Sterky, Fredrik H / Lee, Virginia M Y /
    Lee, Edward B / DeTure, Michael / Dickson, Dennis W / Sharma, Manu / Mok, Sue-Ann / Luo, Wenjie / Zhao, Mingrui / Kampmann, Martin / Gong, Shiaoching / Gan, Li

    Cell

    2024  Volume 187, Issue 10, Page(s) 2446–2464.e22

    Abstract: Tauopathies are age-associated neurodegenerative diseases whose mechanistic underpinnings remain elusive, partially due to a lack of appropriate human models. Here, we engineered human induced pluripotent stem cell (hiPSC)-derived neuronal lines to ... ...

    Abstract Tauopathies are age-associated neurodegenerative diseases whose mechanistic underpinnings remain elusive, partially due to a lack of appropriate human models. Here, we engineered human induced pluripotent stem cell (hiPSC)-derived neuronal lines to express 4R Tau and 4R Tau carrying the P301S MAPT mutation when differentiated into neurons. 4R-P301S neurons display progressive Tau inclusions upon seeding with Tau fibrils and recapitulate features of tauopathy phenotypes including shared transcriptomic signatures, autophagic body accumulation, and reduced neuronal activity. A CRISPRi screen of genes associated with Tau pathobiology identified over 500 genetic modifiers of seeding-induced Tau propagation, including retromer VPS29 and genes in the UFMylation cascade. In progressive supranuclear palsy (PSP) and Alzheimer's Disease (AD) brains, the UFMylation cascade is altered in neurofibrillary-tangle-bearing neurons. Inhibiting the UFMylation cascade in vitro and in vivo suppressed seeding-induced Tau propagation. This model provides a robust platform to identify novel therapeutic strategies for 4R tauopathy.
    MeSH term(s) Humans ; Induced Pluripotent Stem Cells/metabolism ; tau Proteins/metabolism ; Tauopathies/metabolism ; Tauopathies/pathology ; Neurons/metabolism ; Neurons/pathology ; Animals ; Mice ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Alzheimer Disease/genetics ; Brain/metabolism ; Brain/pathology ; Supranuclear Palsy, Progressive/metabolism ; Supranuclear Palsy, Progressive/pathology ; Supranuclear Palsy, Progressive/genetics ; Cell Differentiation ; Mutation ; Autophagy
    Chemical Substances tau Proteins ; MAPT protein, human
    Language English
    Publishing date 2024-04-05
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2024.03.015
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Human iPSC 4R tauopathy model uncovers modifiers of tau propagation.

    Bravo, Celeste Parra / Giani, Alice Maria / Perez, Jesus Madero / Zhao, Zeping / Samelson, Avi / Wong, Man Ying / Evangelisti, Alessandro / Fan, Li / Pozner, Tatyana / Mercedes, Maria / Ye, Pearly / Patel, Tark / Yarahmady, Allan / Carling, Gillian / Lee, Virginia M Y / Sharma, Manu / Mok, Sue-Ann / Luo, Wenjie / Zhao, Mingrui /
    Kampmann, Martin / Gong, Shiaoching / Gan, Li

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Tauopathies are age-associated neurodegenerative diseases whose mechanistic underpinnings remain elusive, partially due to lack of appropriate human models. Current human induced pluripotent stem cell (hiPSC)-derived neurons express very low levels of 4- ... ...

    Abstract Tauopathies are age-associated neurodegenerative diseases whose mechanistic underpinnings remain elusive, partially due to lack of appropriate human models. Current human induced pluripotent stem cell (hiPSC)-derived neurons express very low levels of 4-repeat (4R)-tau isoforms that are normally expressed in adult brain. Here, we engineered new iPSC lines to express 4R-tau and 4R-tau carrying the P301S
    Language English
    Publishing date 2023-06-22
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.06.19.544278
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Tau activation of microglial cGAS-IFN reduces MEF2C-mediated cognitive resilience.

    Udeochu, Joe C / Amin, Sadaf / Huang, Yige / Fan, Li / Torres, Eileen Ruth S / Carling, Gillian K / Liu, Bangyan / McGurran, Hugo / Coronas-Samano, Guillermo / Kauwe, Grant / Mousa, Gergey Alzaem / Wong, Man Ying / Ye, Pearly / Nagiri, Ravi Kumar / Lo, Iris / Holtzman, Julia / Corona, Carlo / Yarahmady, Allan / Gill, Michael T /
    Raju, Ravikiran M / Mok, Sue-Ann / Gong, Shiaoching / Luo, Wenjie / Zhao, Mingrui / Tracy, Tara E / Ratan, Rajiv R / Tsai, Li-Huei / Sinha, Subhash C / Gan, Li

    Nature neuroscience

    2023  Volume 26, Issue 5, Page(s) 737–750

    Abstract: Pathological hallmarks of Alzheimer's disease (AD) precede clinical symptoms by years, indicating a period of cognitive resilience before the onset of dementia. Here, we report that activation of cyclic GMP-AMP synthase (cGAS) diminishes cognitive ... ...

    Abstract Pathological hallmarks of Alzheimer's disease (AD) precede clinical symptoms by years, indicating a period of cognitive resilience before the onset of dementia. Here, we report that activation of cyclic GMP-AMP synthase (cGAS) diminishes cognitive resilience by decreasing the neuronal transcriptional network of myocyte enhancer factor 2c (MEF2C) through type I interferon (IFN-I) signaling. Pathogenic tau activates cGAS and IFN-I responses in microglia, in part mediated by cytosolic leakage of mitochondrial DNA. Genetic ablation of Cgas in mice with tauopathy diminished the microglial IFN-I response, preserved synapse integrity and plasticity and protected against cognitive impairment without affecting the pathogenic tau load. cGAS ablation increased, while activation of IFN-I decreased, the neuronal MEF2C expression network linked to cognitive resilience in AD. Pharmacological inhibition of cGAS in mice with tauopathy enhanced the neuronal MEF2C transcriptional network and restored synaptic integrity, plasticity and memory, supporting the therapeutic potential of targeting the cGAS-IFN-MEF2C axis to improve resilience against AD-related pathological insults.
    MeSH term(s) Animals ; Mice ; Cognition ; Immunity, Innate ; Interferons ; MEF2 Transcription Factors/genetics ; Microglia/metabolism ; Nucleotidyltransferases/genetics ; Nucleotidyltransferases/metabolism ; tau Proteins
    Chemical Substances Interferons (9008-11-1) ; MEF2 Transcription Factors ; Mef2c protein, mouse ; Nucleotidyltransferases (EC 2.7.7.-) ; tau Proteins
    Language English
    Publishing date 2023-04-24
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1420596-8
    ISSN 1546-1726 ; 1097-6256
    ISSN (online) 1546-1726
    ISSN 1097-6256
    DOI 10.1038/s41593-023-01315-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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