Browsing by Subject "Tauopathies"

Now showing 1 - 10 of 14
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    Age-dependent formation of TMEM106B amyloid filaments in human brains
    (Springer Nature, 2022) Schweighauser, Manuel; Arseni, Diana; Bacioglu, Mehtap; Huang, Melissa; Lövestam, Sofia; Shi, Yang; Yang, Yang; Zhang, Wenjuan; Kotecha, Abhay; Garringer, Holly J.; Vidal, Ruben; Hallinan, Grace I.; Newell, Kathy L.; Tarutani, Airi; Murayama, Shigeo; Miyazaki, Masayuki; Saito, Yuko; Yoshida, Mari; Hasegawa, Kazuko; Lashley, Tammaryn; Revesz, Tamas; Kovacs, Gabor G.; van Swieten, John; Takao, Masaki; Hasegawa, Masato; Ghetti, Bernardino; Spillantini, Maria Grazia; Ryskeldi-Falcon, Benjamin; Murzin, Alexey G.; Goedert, Michel; Scheres, Sjors H.W.; Pathology and Laboratory Medicine, School of Medicine
    Many age-dependent neurodegenerative diseases, such as Alzheimer's and Parkinson's, are characterized by abundant inclusions of amyloid filaments. Filamentous inclusions of the proteins tau, amyloid-β, α-synuclein and transactive response DNA-binding protein (TARDBP; also known as TDP-43) are the most common1,2. Here we used structure determination by cryogenic electron microscopy to show that residues 120-254 of the lysosomal type II transmembrane protein 106B (TMEM106B) also form amyloid filaments in human brains. We determined the structures of TMEM106B filaments from a number of brain regions of 22 individuals with abundant amyloid deposits, including those resulting from sporadic and inherited tauopathies, amyloid-β amyloidoses, synucleinopathies and TDP-43 proteinopathies, as well as from the frontal cortex of 3 individuals with normal neurology and no or only a few amyloid deposits. We observed three TMEM106B folds, with no clear relationships between folds and diseases. TMEM106B filaments correlated with the presence of a 29-kDa sarkosyl-insoluble fragment and globular cytoplasmic inclusions, as detected by an antibody specific to the carboxy-terminal region of TMEM106B. The identification of TMEM106B filaments in the brains of older, but not younger, individuals with normal neurology indicates that they form in an age-dependent manner.
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    Cellular localization of p-tau217 in brain and its association with p-tau217 plasma levels
    (BMC, 2022) Wennström, Malin; Janelidze, Shorena; Nilsson, K. Peter R.; The Netherlands Brain Bank; Serrano, Geidy E.; Beach, Thomas G.; Dage, Jeffrey L.; Hansson, Oskar; Neurology, School of Medicine
    Recent studies highlight phosphorylated tau (p-tau) at threonine tau 217 (p-tau217) as a new promising plasma biomarker for pathological changes implicated in Alzheimer's disease (AD), but the specific brain pathological events related to the alteration in p-tau217 plasma levels are still largely unknown. Using immunostaining techniques of postmortem AD brain tissue, we show that p-tau217 is found in neurofibrillary tangles (NFTs) and neuropil threads that are also positive for p-tau181, 202, 202/205, 231, and 369/404. The p-tau217, but not the other five p-tau variants, was also prominently seen in vesicles structure positive for markers of granulovacuolar degeneration bodies and multi-vesicular bodies. Further, individuals with a high likelihood of AD showed significantly higher p-tau217 area fraction in 4 different brain areas (entorhinal cortex, inferior temporal gyrus, and superior frontal gyrus) compared to those with Primary age related tauopathy or other non-AD tauopathies. The p-tau217 area fraction correlated strongly with total amyloid-beta (Aβ) and NFT brain load when the whole group was analyzed. Finally, the mean p-tau217 area fraction correlated significantly with p-tau217 concentrations in antemortem collected plasma specifically in individuals with amyloid plaques and not in those without amyloid plaques. These studies highlight differences in cellular localization of different p-tau variants and suggest that plasma levels of p-tau217 reflect an accumulation of p-tau217 in presence of Aβ plaque load.
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    Cross-β helical filaments of Tau and TMEM106B in gray and white matter of multiple system tauopathy with presenile dementia
    (Springer, 2023) Hoq, Md. Rejaul; Bharath, Sakshibeedu R.; Hallinan, Grace I.; Fernandez, Anllely; Vago, Frank S.; Ozcan, Kadir A.; Li, Daoyi; Garringer, Holly J.; Vidal, Ruben; Ghetti, Bernardino; Jiang, Wen; Pathology and Laboratory Medicine, School of Medicine
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    Genetically enhancing the expression of chemokine domain of CX3CL1 fails to prevent tau pathology in mouse models of tauopathy
    (Biomed Central, 2018-09-25) Maphis, Nicole M.; Formica, Shane V.; Wilson, Gina N.; Miller, Crystal M.; Xu, Guixiang; Kokiko-Cochran, Olga N.; Kim, Ki-Wook; Jung, Steffen; Cannon, Judy L.; Crish, Samuel D.; Cardona, Astrid E.; Lamb, Bruce T.; Bhaskar, Kiran; Bemiller, Shane M.; Medicine, School of Medicine
    BACKGROUND: Fractalkine (CX3CL1) and its receptor (CX3CR1) play an important role in regulating microglial function. We have previously shown that Cx3cr1 deficiency exacerbated tau pathology and led to cognitive impairment. However, it is still unclear if the chemokine domain of the ligand CX3CL1 is essential in regulating neuronal tau pathology. METHODS: We used transgenic mice lacking endogenous Cx3cl1 (Cx3cl1-/-) and expressing only obligatory soluble form (with only chemokine domain) and lacking the mucin stalk of CX3CL1 (referred to as Cx3cl1105Δ mice) to assess tau pathology and behavioral function in both lipopolysaccharide (LPS) and genetic (hTau) mouse models of tauopathy. RESULTS: First, increased basal tau levels accompanied microglial activation in Cx3cl1105Δ mice compared to control groups. Second, increased CD45+ and F4/80+ neuroinflammation and tau phosphorylation were observed in LPS, hTau/Cx3cl1-/-, and hTau/Cx3cl1105Δ mouse models of tau pathology, which correlated with impaired spatial learning. Finally, microglial cell surface expression of CX3CR1 was reduced in Cx3cl1105Δ mice, suggesting enhanced fractalkine receptor internalization (mimicking Cx3cr1 deletion), which likely contributes to the elevated tau pathology. CONCLUSIONS: Collectively, our data suggest that overexpression of only chemokine domain of CX3CL1 does not protect against tau pathology.
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    Globular glial tauopathies (GGT): consensus recommendations
    (Springer, 2013) Ahmed, Zeshan; Bigio, Eileen H.; Budka, Herbert; Dickson, Dennis W.; Ferrer, Isidro; Ghetti, Bernardino; Giaccone, Giorgio; Hatanpaa, Kimmo J.; Holton, Janice L.; Josephs, Keith A.; Powers, James; Spina, Salvatore; Takahashi, Hitoshi; White, Charles L., III; Revesz, Tamas; Kovacs, Gabor G.; Pathology and Laboratory Medicine, School of Medicine
    Recent studies have highlighted a group of 4-repeat (4R) tauopathies that are characterised neuropathologically by widespread, globular glial inclusions (GGIs). Tau immunohistochemistry reveals 4R immunoreactive globular oligodendroglial and astrocytic inclusions and the latter are predominantly negative for Gallyas silver staining. These cases are associated with a range of clinical presentations, which correlate with the severity and distribution of underlying tau pathology and neurodegeneration. Their heterogeneous clinicopathological features combined with their rarity and under-recognition have led to cases characterised by GGIs being described in the literature using various and redundant terminologies. In this report, a group of neuropathologists form a consensus on the terminology and classification of cases with GGIs. After studying microscopic images from previously reported cases with suspected GGIs (n = 22), this panel of neuropathologists with extensive experience in the diagnosis of neurodegenerative diseases and a documented record of previous experience with at least one case with GGIs, agreed that (1) GGIs were present in all the cases reviewed; (2) the morphology of globular astrocytic inclusions was different to tufted astrocytes and finally that (3) the cases represented a number of different neuropathological subtypes. They also agreed that the different morphological subtypes are likely to be part of a spectrum of a distinct disease entity, for which they recommend that the overarching term globular glial tauopathy (GGT) should be used. Type I cases typically present with frontotemporal dementia, which correlates with the fronto-temporal distribution of pathology. Type II cases are characterised by pyramidal features reflecting motor cortex involvement and corticospinal tract degeneration. Type III cases can present with a combination of frontotemporal dementia and motor neuron disease with fronto-temporal cortex, motor cortex and corticospinal tract being severely affected. Extrapyramidal features can be present in Type II and III cases and significant degeneration of the white matter is a feature of all GGT subtypes. Improved detection and classification will be necessary for the establishment of neuropathological and clinical diagnostic research criteria in the future.
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    Interactome Analysis of Tau‐seed Isolated from AD Brains Suggests New Mechanism for Tau Aggregation and Spreading
    (Wiley, 2025-01-03) Martinez, Pablo; You, Yanwen; Patel, Henika; Jury, Nur; Min, Yuhao; Redding, Javier; Huang, Xiaoqing; Dutta, Sayan; Mosley, Amber L.; Rochet, Jean-Christophe; Zhang, Jie; Ertekin-Taner, Nilüfer; Troncoso, Juan C.; Lasagna Reeves, Cristian A.; Anatomy, Cell Biology and Physiology, School of Medicine
    Background: Tau aggregates, a hallmark of Alzheimer’s disease (AD) and other tauopathies, spread throughout the brain, contributing to neurodegeneration. How this propagation occurs remains elusive. Previous research suggests that tau‐seed interactors play a crucial role. Based on this, the study aimed to identify novel tau‐seed interactors in AD brains and validate their impact in vivo. Method: AD and control brain extracts were separated in fractions by Size Exclusion Chromatography. Fractions with the highest tau seeding activity, measured using a tai‐biosensor cell line, were analyzed by mass spectrometry to identify interacting proteins. Bioinformatic tools dissected enriched pathways, identifying interactors that were validated in a Drosophila tauopathy model by genetically interfering with their homologs and assessing tau accumulation and eye degeneration. Results: Tau seeding activity was concentrated in high molecular weight fractions containing only a small portion of total tau in the AD brains. Compared to controls, AD brains revealed a distinct interactome for tau‐seeds, enriched in proteins associated with synaptic and mitochondrial pathways. Notably, Drosophila screening confirmed that several novel interactors significantly reduced tau accumulation and eye degeneration, suggesting their potential therapeutic relevance. Conclusion: This study sheds light on tau propagation mechanisms in AD by identifying novel tau‐seed interactors. These interactors, particularly those involved in synaptic and mitochondrial pathways, offer promising targets for therapeutic interventions aimed at decreasing tau spread and potentially preventing neurodegeneration in tauopathies. The findings add to the growing evidence that targeting tau‐seed interactors, like previously identified BSN, could represent a novel strategy for treating these debilitating conditions.
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    Network analysis identifies strain-dependent response to tau and tau seeding-associated genes
    (Rockefeller University Press, 2023) Acri, Dominic J.; You, Yanwen; Tate, Mason D.; Karahan, Hande; Martinez, Pablo; McCord, Brianne; Sharify, A. Daniel; John, Sutha; Kim, Byungwook; Dabin, Luke C.; Philtjens, Stéphanie; Wijeratne, H. R. Sagara; McCray, Tyler J.; Smith, Daniel C.; Bissel, Stephanie J.; Lamb, Bruce T.; Lasagna-Reeves, Cristian A.; Kim, Jungsu; Anatomy, Cell Biology and Physiology, School of Medicine
    Previous research demonstrated that genetic heterogeneity is a critical factor in modeling amyloid accumulation and other Alzheimer's disease phenotypes. However, it is unknown what mechanisms underlie these effects of genetic background on modeling tau aggregate-driven pathogenicity. In this study, we induced tau aggregation in wild-derived mice by expressing MAPT. To investigate the effect of genetic background on the action of tau aggregates, we performed RNA sequencing with brains of C57BL/6J, CAST/EiJ, PWK/PhJ, and WSB/EiJ mice (n = 64) and determined core transcriptional signature conserved in all genetic backgrounds and signature unique to wild-derived backgrounds. By measuring tau seeding activity using the cortex, we identified 19 key genes associated with tau seeding and amyloid response. Interestingly, microglial pathways were strongly associated with tau seeding activity in CAST/EiJ and PWK/PhJ backgrounds. Collectively, our study demonstrates that mouse genetic context affects tau-mediated alteration of transcriptome and tau seeding. The gene modules associated with tau seeding provide an important resource to better model tauopathy.
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    Novel avenues of tau research
    (Wiley, 2024) Sexton, Claire E.; Bitan, Gal; Bowles, Kathryn R.; Brys, Miroslaw; Buée, Luc; Bukar Maina, Mahmoud; Clelland, Claire D.; Cohen, Ann D.; Crary, John F.; Dage, Jeffrey L.; Diaz, Kristophe; Frost, Bess; Gan, Li; Goate, Alison M.; Golbe, Lawrence I.; Hansson, Oskar; Karch, Celeste M.; Kolb, Hartmuth C.; La Joie, Renaud; Lee, Suzee E.; Matallana, Diana; Miller, Bruce L.; Onyike, Chiadi U.; Quiroz, Yakeel T.; Rexach, Jessica E.; Rohrer, Jonathan D.; Rommel, Amy; Sadri-Vakili, Ghazaleh; Schindler, Suzanne E.; Schneider, Julie A.; Sperling, Reisa A.; Teunissen, Charlotte E.; Weninger, Stacie C.; Worley, Susan L.; Zheng, Hui; Carrillo, Maria C.; Neurology, School of Medicine
    Introduction: The pace of innovation has accelerated in virtually every area of tau research in just the past few years. Methods: In February 2022, leading international tau experts convened to share selected highlights of this work during Tau 2022, the second international tau conference co-organized and co-sponsored by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation. Results: Representing academia, industry, and the philanthropic sector, presenters joined more than 1700 registered attendees from 59 countries, spanning six continents, to share recent advances and exciting new directions in tau research. Discussion: The virtual meeting provided an opportunity to foster cross-sector collaboration and partnerships as well as a forum for updating colleagues on research-advancing tools and programs that are steadily moving the field forward.
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    Optimal Transport‐Based Transcriptomic Mapping Revealed Atypical Disease Progression Subtypes in Living Alzheimer’s Disease Patients
    (Wiley, 2025-01-09) Huang, Xiaoqing; Zhang, Jie; Huang, Kun; Lasagna Reeves, Cristian A.; Jury, Nur; Medical and Molecular Genetics, School of Medicine
    Background: Alzheimer’s disease (AD) exhibits substantial heterogeneity in its disease trajectory. A subset of AD patients with unmatched cognitive decline/tauopathy severity has not been well studied. We identified such atypical subgroups in post‐mortem AD brain studies. However, such atypical subtypes may not be easily identified in living patients, as obtaining brain samples are unfeasible, and NFT measurement is not accurate. In this study, we utilize the matched transcriptomic data from both brain and blood of ROSMAP cohort to identify such atypical AD groups in the blood transcriptomic data of live patients in other cohorts using transfer learning‐based approach, to uncover distinct molecular signatures and biomarkers for earlier and more accurate disease subtyping and prognosis in living AD patients. Method: Three subgroups were defined from ROSMAP cohort with the blood and brain RNA‐seq data based on the clinical information of their tauopathies and disease progression, namely, Asymptomatic AD, Low‐NFT AD, Typical AD, plus normal Control, which serves as our training dataset for a supervised transfer learning. Then, the labels were transferred to the blood RNA‐seq samples from two new cohorts, ADNI and ANMerge using optimal transport. Next, we identify the genes consistently expressed in three independent cohorts for that specific AD subtype. Lastly, the diffusion pseudo‐time analysis infers the temporal order of the gene expression patterns within each subgroups. Dominant genes with a consistent expression pattern across cohorts are considered as the signature for each subgroup, and their relevance to AD pathology is analyzed. Result: We identified distinctive genes with consistent expression patterns across cohorts for each AD subgroup. Remarkably, our analysis also reveals the temporal gene expression dynamics differs for sex, age (late/early onset), and onset pattern (sudden/gradual) across the cohorts. Conclusion: Through a deep transfer learning‐based approach on the blood and brain transcriptomic data, we successfully identified the atypical disease progression subgroups among live AD patient cohorts in ADNI and ANMerge with promising biomarkers/gene signatures. The molecular signatures identified in this study not only enhance our comprehension of the underlying pathophysiological mechanisms but also hold promise for developing early prognosis and effective personalized treatments for AD and related tauopathies.
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    Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology
    (BioMed Central, 2016-12-15) Maphis, Nicole; Jiang, Shanya; Xu, Guixiang; Kokiko-Cochran, Olga N.; Roy, Saktimayee M.; Van Eldik, Linda J.; Watterson, D. Martin; Lamb, Bruce T.; Bhaskar, Kiran; Department of Medicine, IU School of Medicine
    BACKGROUND: Hyperphosphorylation and aggregation of tau protein are the pathological hallmarks of Alzheimer's disease and related tauopathies. We previously demonstrated that the microglial activation induces tau hyperphosphorylation and cognitive impairment via activation of p38 mitogen-activated protein kinase (p38 MAPK) in the hTau mouse model of tauopathy that was deficient for microglial fractalkine receptor CX3CR1. METHOD: We report an isoform-selective, brain-permeable, and orally bioavailable small molecule inhibitor of p38α MAPK (MW181) and its effects on tau phosphorylation in vitro and in hTau mice. RESULTS: First, pretreatment of mouse primary cortical neurons with MW181 completely blocked inflammation-induced p38α MAPK activation and AT8 (pS199/pS202) site tau phosphorylation, with the maximum effect peaking at 60-90 min after stimulation. Second, treatment of old (~20 months of age) hTau mice with MW181 (1 mg/kg body weight; 14 days via oral gavage) significantly reduced p38α MAPK activation compared with vehicle-administered hTau mice. This also resulted in a significant reduction in AT180 (pT231) site tau phosphorylation and Sarkosyl-insoluble tau aggregates. Third, MW181 treatment significantly increased synaptophysin protein expression and resulted in improved working memory. Fourth, MW181 administration reduced phosphorylated MAPK-activated protein kinase 2 (pMK2) and phosphorylated activating transcription factor 2 (pATF2), which are known substrates of p38α MAPK. Finally, MW181 reduced the expression of interferon-γ and interleukin-1β. CONCLUSIONS: Taken together, these studies support p38α MAPK as a valid therapeutic target for the treatment of tauopathies.