Erratum to “Neurofibrillary tangle-like tau pathology induced by synthetic tau fibrils in primary neurons over-expressing mutant tau” [FEBS Lett. 587 (2013) pp 717-723]

FEBS Letters ◽  
2013 ◽  
Vol 587 (15) ◽  
pp. 2484-2484
Author(s):  
Jing L. Guo ◽  
Virginia M.Y. Lee
Keyword(s):  
Neurofibrillary Tangle ◽  
Primary Neurons ◽  
Tau Pathology ◽  
Tau Fibrils

scholarly journals Onset of hippocampal network aberration and memory deficits in P301S tau mice are associated with an early gene signature

Brain ◽  
2020 ◽  
Vol 143 (6) ◽  
pp. 1889-1904
Author(s):  
Magdalena Przybyla ◽  
Janet van Eersel ◽  
Annika van Hummel ◽  
Julia van der Hoven ◽  
Miheer Sabale ◽  
...  
Keyword(s):  
Neuronal Network ◽  
Neurofibrillary Tangle ◽  
Memory Deficits ◽  
Long Term Potentiation ◽  
Gene Signature ◽  
Early Gene ◽  
Immediate Early ◽  
Tau Pathology ◽  
Network Function ◽  
Mapt Gene

Abstract Hyperphosphorylation and deposition of tau in the brain characterizes frontotemporal dementia and Alzheimer’s disease. Disease-associated mutations in the tau-encoding MAPT gene have enabled the generation of transgenic mouse models that recapitulate aspects of human neurodegenerative diseases, including tau hyperphosphorylation and neurofibrillary tangle formation. Here, we characterized the effects of transgenic P301S mutant human tau expression on neuronal network function in the murine hippocampus. Onset of progressive spatial learning deficits in P301S tau transgenic TAU58/2 mice were paralleled by long-term potentiation deficits and neuronal network aberrations during electrophysiological and EEG recordings. Gene-expression profiling just prior to onset of apparent deficits in TAU58/2 mice revealed a signature of immediate early genes that is consistent with neuronal network hypersynchronicity. We found that the increased immediate early gene activity was confined to neurons harbouring tau pathology, providing a cellular link between aberrant tau and network dysfunction. Taken together, our data suggest that tau pathology drives neuronal network dysfunction through hyperexcitation of individual, pathology-harbouring neurons, thereby contributing to memory deficits.

scholarly journals Conformation-selective tau monoclonal antibodies inhibit tau pathology in primary neurons and a mouse model of Alzheimer’s disease

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Garrett S. Gibbons ◽  
Soo-Jung Kim ◽  
Qihui Wu ◽  
Dawn M. Riddle ◽  
Susan N. Leight ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Monoclonal Antibodies ◽  
Statistical Significance ◽  
Neuritic Plaque ◽  
Plaque Burden ◽  
Primary Neurons ◽  
Tau Pathology ◽  
Model Of Alzheimer’S Disease

Abstract Background The spread of tau pathology in Alzheimer’s disease (AD) is mediated by cell-to-cell transmission of pathological tau seeds released from neurons that, upon internalization by recipient neurons, template the misfolding of naïve cellular tau, thereby propagating fibrillization. We hypothesize that anti-tau monoclonal antibodies (mAbs) that selectively bind to pathological tau seeds will inhibit propagation of tau aggregates and reduce the spread of tau pathology in vivo. Methods We inoculated mice with human AD brain-derived extracts containing tau paired helical filaments (AD-tau) and identified two novel mAbs, DMR7 and SKT82, that selectively bind to a misfolded pathological conformation of tau relative to recombinant tau monomer. To evaluate the effects of these mAbs on the spread of pathological tau in vivo, 5xFAD mice harboring significant brain Aβ plaque burden were unilaterally injected with AD-tau in the hippocampus, to initiate the formation of neuritic plaque (NP) tau pathology, and were treated weekly with intraperitoneal (i.p.) injections of DMR7, SKT82, or IgG isotype control mAbs. Results DMR7 and SKT82 bind epitopes comprised of the proline-rich domain and c-terminal region of tau and binding is reduced upon disruption of the pathological conformation of AD-tau by chemical and thermal denaturation. We found that both DMR7 and SKT82 immunoprecipitate pathological tau and significantly reduce the seeding of cellular tau aggregates induced by AD-tau in primary neurons by 60.5 + 13.8% and 82.2 + 8.3%, respectively, compared to IgG control. To investigate the mechanism of mAb inhibition, we generated pH-sensitive fluorophore-labeled recombinant tau fibrils seeded by AD-tau to track internalization of tau seeds and demonstrate that the conformation-selective tau mAbs inhibit the internalization of tau seeds. DMR7 and SKT82 treatment reduced hyperphosphorylated NP tau as measured with AT8 immunohistochemistry (IHC) staining, but did not achieve statistical significance in the contralateral cortex and SKT82 significantly reduced tau pathology in the ipsilateral hippocampus by 24.2%; p = 0.044. Conclusions These findings demonstrate that conformation-selective tau mAbs, DMR7 and SKT82, inhibit tau pathology in primary neurons by preventing the uptake of tau seeds and reduce tau pathology in vivo, providing potential novel therapeutic candidates for the treatment of AD.

scholarly journals Tau pathology spread in PS19 tau transgenic mice following locus coeruleus (LC) injections of synthetic tau fibrils is determined by the LC’s afferent and efferent connections

2015 ◽  
Vol 130 (3) ◽  
pp. 349-362 ◽  
Author(s):  
Michiyo Iba ◽  
Jennifer D. McBride ◽  
Jing L. Guo ◽  
Bin Zhang ◽  
John Q. Trojanowski ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Locus Coeruleus ◽  
Tau Pathology ◽  
Efferent Connections ◽  
Tau Fibrils

scholarly journals Unique pathological tau conformers from Alzheimer’s brains transmit tau pathology in nontransgenic mice

2016 ◽  
Vol 213 (12) ◽  
pp. 2635-2654 ◽  
Author(s):  
Jing L. Guo ◽  
Sneha Narasimhan ◽  
Lakshmi Changolkar ◽  
Zhuohao He ◽  
Anna Stieber ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Cell Culture ◽  
Mouse Model ◽  
Neurodegenerative Diseases ◽  
Animal Studies ◽  
Brain Regions ◽  
Tau Pathology ◽  
Intracerebral Inoculation ◽  
Cell Transmission ◽  
Tau Fibrils

Filamentous tau aggregates are hallmark lesions in numerous neurodegenerative diseases, including Alzheimer’s disease (AD). Cell culture and animal studies showed that tau fibrils can undergo cell-to-cell transmission and seed aggregation of soluble tau, but this phenomenon was only robustly demonstrated in models overexpressing tau. In this study, we found that intracerebral inoculation of tau fibrils purified from AD brains (AD-tau), but not synthetic tau fibrils, resulted in the formation of abundant tau inclusions in anatomically connected brain regions in nontransgenic mice. Recombinant human tau seeded by AD-tau revealed unique conformational features that are distinct from synthetic tau fibrils, which could underlie the differential potency in seeding physiological levels of tau to aggregate. Therefore, our study establishes a mouse model of sporadic tauopathies and points to important differences between tau fibrils that are generated artificially and authentic ones that develop in AD brains.

scholarly journals Differential cross-seeding properties of tau and α-synuclein in mouse models of tauopathy and synucleinopathy

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Tosha Williams ◽  
Zachary Sorrentino ◽  
Mary Weinrich ◽  
Benoit I Giasson ◽  
Paramita Chakrabarty
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Phosphorylated Tau ◽  
Tau Pathology ◽  
Whole Brain ◽  
Transmission Properties ◽  
Priming Process ◽  
Robust Transmission ◽  
Cooperative Relationship ◽  
Tau Fibrils

Abstract Co-occurrence of tau and α-synuclein pathologies in a subset of Alzheimer’s disease patients has led to the idea that mixed pathologies may play a unique characteristic role in the Alzheimer’s disease neurodegenerative cascade. To understand the aetiology of such mixed pathologies, we investigated cross-seeding by human recombinant tau and human recombinant α-synuclein fibrillar species in a mouse model of tauopathy (Line PS19) or synucleinopathy (Line M20). Unilateral hippocampal injection of tau fibrils or α-synuclein fibrils, and to a lesser extent tau + α-synuclein copolymer fibrils prepared from co-incubating individual recombinant monomers, induced robust phosphorylated tau pathology in PS19 mice relative to control mice. Though the tau + α-synuclein copolymer fibrils did not modulate induction of pathologies at the site of injection, examination of the whole brain showed that these copolymers exacerbated neuroanatomic transmission of seeded tau pathology compared to tau fibril-injected mice. Only α-synuclein fibrils, but not tau alone or tau + α-synuclein copolymers, triggered modest levels of endogenous phosphorylated α-synuclein pathology. Overall, data from the PS19 mice suggest that human α-synuclein fibrils can efficiently cross-seed human tau and have a modest priming effect on mouse α-synuclein, and the presence of tau fibrils does not exacerbate the priming process. In M20 mice, unilateral hippocampal injection of α-synuclein fibrils or tau fibrils induced robust bilateral phosphorylated α-synuclein pathology, while tau + α-synuclein copolymer injection resulted in restricted phosphorylated α-synuclein pathology predominantly in the ipsilateral cortex. This suggests that human tau fibrils can also induce human α-synuclein pathogenesis, and the presence of combinatorial seeds is not synergistic. None of these aggregates induced phosphorylated tau pathology in M20 mice, showing that mouse tau cannot be primed efficiently by human tau fibrils or human α-synuclein fibrils. Neuropathological analysis of the whole brain of M20 mice showed that tau + α-synuclein copolymer-injected mice had lower abundance of bilaterally transmitted α-synuclein pathologies relative to α-synuclein fibril-injected mice. Thus, the tau + α-synuclein copolymer fibrils show robust transmission properties preferentially in rodent model of tauopathies but not in synucleinopathy, probably signifying an enhanced cooperative relationship between tau and α-synuclein in the tau seeding process. Together, our data highlight the unique cross-seeding properties of tau and αSyn in neurodegenerative proteinopathies.

scholarly journals 18F-flortaucipir PET to autopsy comparisons in Alzheimer’s disease and other neurodegenerative diseases

Brain ◽  
2020 ◽  
Vol 143 (11) ◽  
pp. 3477-3494 ◽  
Author(s):  
David N Soleimani-Meigooni ◽  
Leonardo Iaccarino ◽  
Renaud La Joie ◽  
Suzanne Baker ◽  
Viktoriya Bourakova ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Progressive Supranuclear Palsy ◽  
Frontotemporal Lobar Degeneration ◽  
Neurofibrillary Tangle ◽  
Corticobasal Degeneration ◽  
Braak Stage ◽  
Tau Pathology ◽  
Cognitively Normal ◽  
Normal Controls

Abstract Few studies have evaluated the relationship between in vivo18F-flortaucipir PET and post-mortem pathology. We sought to compare antemortem 18F-flortaucipir PET to neuropathology in a consecutive series of patients with a broad spectrum of neurodegenerative conditions. Twenty patients were included [mean age at PET 61 years (range 34–76); eight female; median PET-to-autopsy interval of 30 months (range 4–59 months)]. Eight patients had primary Alzheimer’s disease pathology, nine had non-Alzheimer tauopathies (progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, and frontotemporal lobar degeneration with MAPT mutations), and three had non-tau frontotemporal lobar degeneration. Using an inferior cerebellar grey matter reference, 80–100-min 18F-flortaucipir PET standardized uptake value ratio (SUVR) images were created. Mean SUVRs were calculated for progressive supranuclear palsy, corticobasal degeneration, and neurofibrillary tangle Braak stage regions of interest, and these values were compared to SUVRs derived from young, non-autopsy, cognitively normal controls used as a standard for tau negativity. W-score maps were generated to highlight areas of increased tracer retention compared to cognitively normal controls, adjusting for age as a covariate. Autopsies were performed blinded to PET results. There was excellent correspondence between areas of 18F-flortaucipir retention, on both SUVR images and W-score maps, and neurofibrillary tangle distribution in patients with primary Alzheimer’s disease neuropathology. Patients with non-Alzheimer tauopathies and non-tau frontotemporal lobar degeneration showed a range of tracer retention that was less than Alzheimer’s disease, though higher than age-matched, cognitively normal controls. Overall, binding across both tau-positive and tau-negative non-Alzheimer disorders did not reliably correspond with post-mortem tau pathology. 18F-flortaucipir SUVRs in subcortical regions were higher in autopsy-confirmed progressive supranuclear palsy and corticobasal degeneration than in controls, but were similar to values measured in Alzheimer’s disease and tau-negative neurodegenerative pathologies. Quantification of 18F-flortaucipir SUVR images at Braak stage regions of interest reliably detected advanced Alzheimer’s (Braak VI) pathology. However, patients with earlier Braak stages (Braak I–IV) did not show elevated tracer uptake in these regions compared to young, tau-negative controls. In summary, PET-to-autopsy comparisons confirm that 18F-flortaucipir PET is a reliable biomarker of advanced Braak tau pathology in Alzheimer’s disease. The tracer cannot reliably differentiate non-Alzheimer tauopathies and may not detect early Braak stages of neurofibrillary tangle pathology.

scholarly journals LRRK2 Kinase Activity Does Not Alter Cell-Autonomous Tau Pathology Development in Primary Neurons

2021 ◽  
pp. 1-10
Author(s):  
Michael X. Henderson ◽  
Lakshmi Changolkar ◽  
John Q. Trojanowski ◽  
Virginia M.Y. Lee
Keyword(s):  
Kinase Activity ◽  
Kinase Inhibitors ◽  
Lewy Bodies ◽  
Primary Neurons ◽  
Tau Pathology ◽  
Therapeutic Development ◽  
Lrrk2 Kinase ◽  
A Minor ◽  
The Impact ◽  
Lrrk2 Kinase Activity

Background: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson’s disease (PD) and are also associated with genetic risk in idiopathic PD. Mutations in LRRK2, including the most common p.G2019S lead to elevated kinase activity, making LRRK2 kinase inhibitors prime targets for therapeutic development. However, the role of LRRK2 kinase activity in PD pathogenesis has remained unclear. While essentially all LRRK2-PD patients exhibit dopaminergic neuron loss, many of these patients to not have α-synuclein Lewy bodies in their brains. So, what is the neuropathological substrate of LRRK2-PD? Tau has emerged as a possible candidate due to the presence of tau pathology in the majority of LRRK2 mutation carriers and reports of hyperphosphorylated tau in LRRK2 animal models. Objective: In the current study, we aim to address whether a mutation in LRRK2 changes the cell-autonomous seeding of tau pathology in primary neurons. We also aim to assess whether LRRK2 kinase inhibitors are able to modulate tau pathology. Methods/Results: Treatment of primary neurons with LRRK2 kinase inhibitors leads to prolonged kinase inhibition but does not alter tau pathology induction. The lack of an effect of LRRK2 kinase activity was further confirmed in primary neurons expressing LRRK2G2019S and with two different forms of pathogenic tau. In no case was there more than a minor change in tau pathology induction. Conclusion: Together, our results indicate that LRRK2 kinase activity is not playing a major role in the induction of tau pathology in individual neurons. Understanding the impact of LRRK2 kinase inhibitors on pathology generation is important as kinase inhibitors move forward in clinical trials.

scholarly journals Evaluating Effects of Glatiramer Acetate Treatment on Amyloid Deposition and Tau Phosphorylation in the 3xTg Mouse Model of Alzheimer’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Dawling A. Dionisio-Santos ◽  
Berke Karaahmet ◽  
Elizabeth K. Belcher ◽  
Laura D. Owlett ◽  
Lee A. Trojanczyk ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glatiramer Acetate ◽  
Neurofibrillary Tangle ◽  
Subcutaneous Administration ◽  
Amyloid Β ◽  
Tau Phosphorylation ◽  
Striking Difference ◽  
Tau Pathology ◽  
Model Of Alzheimer’S Disease

Neuroinflammation driven by the accumulation of amyloid β (Aβ) can lead to neurofibrillary tangle formation in Alzheimer’s Disease (AD). To test the hypothesis that an anti-inflammatory immunomodulatory agent might have beneficial effects on amyloid and tau pathology, as well as microglial phenotype, we evaluated glatiramer acetate (GA), a multiple sclerosis drug thought to bias type 2 helper T (Th2) cell responses and alternatively activate myeloid cells. We administered weekly subcutaneous injections of GA or PBS to 15-month-old 3xTg AD mice, which develop both amyloid and tau pathology, for a period of 8 weeks. We found that subcutaneous administration of GA improved behavioral performance in novel object recognition and decreased Aβ plaque in the 3xTg AD mice. Changes in tau phosphorylation were mixed with specific changes in phosphoepitopes seen in immunohistochemistry but not observed in western blot. In addition, we found that there was a trend toward increased microglia complexity in 3xTg mice treated with GA, suggesting a shift toward homeostasis. These findings correlated with subtle changes in the microglial transcriptome, in which the most striking difference was the upregulation of Dcstamp. Lastly, we found no evidence of changes in proportions of major helper T cell (Th) subtypes in the periphery. Overall, our study provides further evidence for the benefits of immunomodulatory therapies that alter the adaptive immune system with the goal of modifying microglia responses for the treatment of Alzheimer’s Disease.

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