scholarly journals Human tau pathology transmits glial tau aggregates in the absence of neuronal tau

2019 ◽  
Vol 217 (2) ◽  
Author(s):  
Sneha Narasimhan ◽  
Lakshmi Changolkar ◽  
Dawn M. Riddle ◽  
Alexandra Kats ◽  
Anna Stieber ◽  
...  
Keyword(s):  
White Matter ◽  
Mouse Model ◽  
Mouse Brain ◽  
Tau Protein ◽  
Corticobasal Degeneration ◽  
Cell Loss ◽  
Tau Pathology ◽  
Abnormal Accumulation ◽  
Nontg Mouse ◽  
Functional Consequences

Tauopathies are characterized by abnormal accumulation of tau protein in neurons and glia. In Alzheimer’s disease (AD), tau aggregates in neurons, while in corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), tau also aggregates in astrocytes and oligodendrocytes. We previously demonstrated that human CBD and PSP tauopathy lysates (CBD-tau and PSP-tau) contain distinct tau strains that propagate neuronal and glial tau aggregates in nontransgenic (nonTg) mouse brain. Yet the mechanism of glial tau transmission is unknown. Here, we developed a novel mouse model to knock down tau in neurons to test for glial tau transmission. While oligodendroglial tau pathology propagated across the mouse brain in the absence of neuronal tau pathology, astrocytic tau pathology did not. Oligodendroglial tau aggregates propagated along white matter tracts independently of neuronal axons, and resulted in oligodendrocyte cell loss. Thus, glial tau pathology has significant functional consequences independent of neuronal tau pathology.

scholarly journals Anti-Aβ antibodies bound to neuritic plaques enhance microglia activity and mitigate tau pathology

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Vanessa Laversenne ◽  
Sameer Nazeeruddin ◽  
Emma C. Källstig ◽  
Philippe Colin ◽  
Christel Voize ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tau Protein ◽  
Hippocampal Formation ◽  
Dystrophic Neurites ◽  
Neuritic Plaques ◽  
Tau Pathology ◽  
Continuous Administration ◽  
Plaque Deposition ◽  
5Xfad Mice

AbstractThe brain pathology of Alzheimer’s disease (AD) is characterized by the misfolding and aggregation of both the amyloid beta (Aβ) peptide and hyperphosphorylated forms of the tau protein. Initial Aβ deposition is considered to trigger a sequence of deleterious events contributing to tau pathology, neuroinflammation and ultimately causing the loss of synapses and neurons. To assess the effect of anti-Aβ immunization in this context, we generated a mouse model by overexpressing the human tau protein in the hippocampus of 5xFAD mice. Aβ plaque deposition combined with human tau overexpression leads to an array of pathological manifestations including the formation of tau-positive dystrophic neurites and accumulation of hyperphosphorylated tau at the level of neuritic plaques. Remarkably, the presence of human tau reduces microglial clustering in proximity to the Aβ plaques, which may affect the barrier role of microglia. In this mouse model, continuous administration of anti-Aβ antibodies enhances the clustering of microglial cells even in the presence of tau. Anti-Aβ immunization increases plaque compaction, reduces the spread of tau in the hippocampal formation and prevents the formation of tau-positive dystrophic neurites. However, the treatment does not significantly reduce tau-induced neurodegeneration in the dentate gyrus. These results highlight that anti-Aβ immunization is able to enhance microglial activity around neuritic plaques, mitigating part of the tau-induced pathological manifestations.

scholarly journals Tauopathies: One Disease or Many?

2011 ◽  
Vol 38 (4) ◽  
pp. 547-556 ◽  
Author(s):  
Manon Bouchard ◽  
Oksana Suchowersky
Keyword(s):  
Progressive Supranuclear Palsy ◽  
Tau Protein ◽  
Clinical Result ◽  
Frontotemporal Lobar Degeneration ◽  
Disease Process ◽  
Corticobasal Degeneration ◽  
Pathological Lesions ◽  
Abnormal Accumulation ◽  
Genetic Features ◽  
The Brain

Tauopathies are a group of disorders that have in common abnormal accumulation of tau protein in the brain. Although the different tauopathies have long been considered to be separate diseases, it is now clear that progressive supranuclear palsy, corticobasal degeneration and some forms of tau-positive frontotemporal lobar degeneration share clinical, pathological and genetic features. The important overlap between these disorders suggest they may represent different phenotypes of a single disease process, the clinical result depending on the topography of pathological lesions as well as other unknown factors.

Tau gene mutations and neurodegeneration

2001 ◽  
Vol 67 ◽  
pp. 59-71 ◽  
Author(s):  
Michel Goedert ◽  
Maria Grazia Spillantini
Keyword(s):  
Tau Protein ◽  
Donor Site ◽  
Gene Mutations ◽  
Corticobasal Degeneration ◽  
Chromosome 17 ◽  
Splice Donor Site ◽  
Coding Region ◽  
Tau Pathology ◽  
Tau Isoforms ◽  
Exon 10

Abundant neurofibrillary lesions made of the microtubule-associated protein tau constitute a defining neuropathological characteristic of Alzheimer's disease. Filamentous tau protein deposits are also the defining neuropathological characteristic of other neurodegenerative diseases, many of which are frontotemporal dementias or movement disorders, such as Pick's disease, progressive supranuclear palsy and corticobasal degeneration. It is well established that the distribution of tau pathology correlates with the presence of symptoms of disease. However, until recently, there was no genetic evidence linking dysfunction of tau protein to neurodegeneration and dementia. This has now changed with the discovery of close to 20 mutations in the tau gene in frontotemporal dementia with Parkinsonism linked to chromosome 17. All cases with tau mutations examined to date have shown an abundant filamentous tau pathology in brain cells. Pathological heterogeneity is determined to a large extent by the location of mutations in tau. Known mutations are either coding region or intronic mutations located close to the splice-donor site of the intron downstream of exon 10. Most coding region mutations produce a reduced ability of tau to interact with microtubules. Several of these mutations also promote sulphated glycosaminoglycan-induced assembly of tau into filaments. Intronic mutations and some coding region mutations produce increased splicing in of exon 10, resulting in an overexpression of four-repeat tau isoforms. Thus a normal ratio of three-repeat to four-repeat tau isoforms is essential for preventing the development of tau pathology. The new work has shown that dysfunction of tau protein can cause neurodegeneration and dementia.

scholarly journals Repetitive Concussive and Subconcussive Injury in a Human Tau Mouse Model Results in Chronic Cognitive Dysfunction and Disruption of White Matter Tracts, But Not Tau Pathology

2019 ◽  
Vol 36 (5) ◽  
pp. 735-755 ◽  
Author(s):  
Mihika Gangolli ◽  
Joseph Benetatos ◽  
Thomas J. Esparza ◽  
Emeka M. Fountain ◽  
Shamilka Seneviratne ◽  
...  
Keyword(s):  
White Matter ◽  
Mouse Model ◽  
Cognitive Dysfunction ◽  
Tau Pathology ◽  
White Matter Tracts ◽  
Subconcussive Injury ◽  
Tau Mouse Model

scholarly journals DTI reveals whole-brain microstructural changes in the P301L mouse model of tauopathy

2020 ◽  
Author(s):  
Aidana Massalimova ◽  
Ruiqing Ni ◽  
Roger M. Nitsch ◽  
Marco Reisert ◽  
Dominik von Elverfeldt ◽  
...  
Keyword(s):  
White Matter ◽  
High Resolution ◽  
Mouse Model ◽  
Mouse Brain ◽  
Diffusion Tensor ◽  
Ex Vivo ◽  
Brain Regions ◽  
Brain Atlas ◽  
Microstructural Changes ◽  
Allen Mouse Brain Atlas

AbstractIntroductionIncreased expression of hyperphosphorylated tau and the formation of neurofibrillary tangles are associated with neuronal loss and white matter damage. Using high resolution ex vivo diffusion tensor imaging (DTI), we investigated microstructural changes in the white and grey matter in the P301L mouse model of human tauopathy at 8.5 months-of-age. For unbiased computational analysis, we implemented a pipeline for voxel-based analysis (VBA) and atlas-based analysis (ABA) of DTI mouse brain data.MethodsHemizygous and homozygous transgenic P301L mice and non-transgenic littermates were used. DTI data were acquired for generation of fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD) maps. VBA on the entire brain were performed using SPM8 and SPM Mouse toolbox. Initially, all DTI maps were co-registered with Allen mouse brain atlas to bring them to one common coordinate space. In VBA, co-registered DTI maps were normalized and smoothed in order to perform two-sample t-tests to compare hemizygotes with non-transgenic littermates, homozygotes with non-transgenic littermates, hemizygotes with homozygotes on each DTI parameter map. In ABA, the average values for selected regions-of-interests were computed with co-registered DTI maps and labels in Allen mouse brain atlas. After, the same two-sample t-tests were executed on the estimated average values.ResultsWe made reconstructed DTI data and VBA and ABA pipeline publicly available. With VBA, we found microstructural changes in the white matter in hemizygous P301L mice compared to non-transgenic littermates. In contrast, more pronounced and brain-wide spread changes were observed in VBA when comparing homozygous P301L mice with non-transgenic littermates. Statistical comparison of DTI metrics in selected brain regions by ABA corroborated findings from VBA. FA was found to be decreased in most brain regions, while MD, RD and AD were increased compared to hemizygotes and non-transgenic littermates.Discussion/ConclusionHigh resolution ex vivo DTI demonstrated brain-wide microstructural changes in the P301L mouse model of human tauopathy. The comparison between hemizygous and homozygous P301L mice revealed a gene-dose dependent effect on DTI metrics. The publicly available computational data analysis pipeline can provide a platform for future mechanistic and longitudinal studies.

scholarly journals Deep learning reveals disease-specific signatures of white matter pathology in tauopathies

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Anthony R. Vega ◽  
Rati Chkheidze ◽  
Vipul Jarmale ◽  
Ping Shang ◽  
Chan Foong ◽  
...  
Keyword(s):  
Machine Learning ◽  
White Matter ◽  
Gray Matter ◽  
Corticobasal Degeneration ◽  
Disease Classification ◽  
Strongly Correlated ◽  
Tau Pathology ◽  
Machine Learning Approach ◽  
Aggregate Morphology ◽  
Disease Specific

AbstractAlthough pathology of tauopathies is characterized by abnormal tau protein aggregation in both gray and white matter regions of the brain, neuropathological investigations have generally focused on abnormalities in the cerebral cortex because the canonical aggregates that form the diagnostic criteria for these disorders predominate there. This corticocentric focus tends to deemphasize the relevance of the more complex white matter pathologies, which remain less well characterized and understood. We took a data-driven machine-learning approach to identify novel disease-specific morphologic signatures of white matter aggregates in three tauopathies: Alzheimer disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). We developed automated approaches using whole slide images of tau immunostained sections from 49 human autopsy brains (16 AD,13 CBD, 20 PSP) to identify cortex/white matter regions and individual tau aggregates, and compared tau-aggregate morphology across these diseases. Tau burden in the gray and white matter for individual subjects strongly correlated in a highly disease-specific fashion. We discovered previously unrecognized tau morphologies for AD, CBD and PSP that may be of importance in disease classification. Intriguingly, our models classified diseases equally well based on either white or gray matter tau staining. Our results suggest that tau pathology in white matter is informative, disease-specific, and linked to gray matter pathology. Machine learning has the potential to reveal latent information in histologic images that may represent previously unrecognized patterns of neuropathology, and additional studies of tau pathology in white matter could improve diagnostic accuracy.

scholarly journals In vitro amplification of pathogenic tau conserves disease-specific bioactive characteristics

2021 ◽  
Author(s):  
Hong Xu ◽  
Mia O’Reilly ◽  
Garrett S. Gibbons ◽  
Lakshmi Changolkar ◽  
Jennifer D. McBride ◽  
...  
Keyword(s):  
Tau Protein ◽  
Biological Activities ◽  
Corticobasal Degeneration ◽  
Tau Pathology ◽  
Protein Tau ◽  
Beta Sheet Structure ◽  
Sheet Structure ◽  
Strain Dependent ◽  
Disease Specific

AbstractThe microtubule-associated protein tau (tau) forms hyperphosphorylated aggregates in the brains of tauopathy patients that can be pathologically and biochemically defined as distinct tau strains. Recent studies show that these tau strains exhibit strain-specific biological activities, also referred to as pathogenicities, in the tau spreading models. Currently, the specific pathogenicity of human-derived tau strains cannot be fully recapitulated by synthetic tau preformed fibrils (pffs), which are generated from recombinant tau protein. Reproducing disease-relevant tau pathology in cell and animal models necessitates the use of human brain-derived tau seeds. However, the availability of human-derived tau is extremely limited. Generation of tau variants that can mimic the pathogenicity of human-derived tau seeds would significantly extend the scale of experimental design within the field of tauopathy research. Previous studies have demonstrated that in vitro seeding reactions can amplify the beta-sheet structure of tau protein from a minute quantity of human-derived tau. However, whether the strain-specific pathogenicities of the original, human-derived tau seeds are conserved in the amplified tau strains has yet to be experimentally validated. Here, we used biochemically enriched brain-derived tau seeds from Alzheimer’s disease (AD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) patient brains with a modified seeding protocol to template the recruitment of recombinant 2N4R (T40) tau in vitro. We quantitatively interrogated efficacy of the amplification reactions and the pathogenic fidelity of the amplified material to the original tau seeds using recently developed sporadic tau spreading models. Our data suggest that different tau strains can be faithfully amplified in vitro from tau isolated from different tauopathy brains and that the amplified tau variants retain their strain-dependent pathogenic characteristics.

scholarly journals Atrophy associated with tau pathology precedes overt cell death in a mouse model of progressive tauopathy

2020 ◽  
Author(s):  
Christine W. Fung ◽  
Jia Guo ◽  
Helen Y. Figueroa ◽  
Elisa E. Konofagou ◽  
Karen E. Duff
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Entorhinal Cortex ◽  
Ex Vivo ◽  
Cell Loss ◽  
Temporal Association ◽  
Tau Pathology ◽  
Model Of Alzheimer’S Disease

AbstractIn the early stages of Alzheimer’s disease (AD), tau pathology first develops in the entorhinal cortex (EC), then spreads to the hippocampus and at later stages, to the neocortex. Pathology in the neocortex correlates with impaired cognitive performance. Overall, tau pathology correlates well with neurodegeneration but the spatial and temporal association between tau pathology and overt volume loss is unclear. Using in vivo magnetic resonance imaging (MRI) with tensor-based morphometry (TBM) we mapped the spatio-temporal pattern of structural changes in a mouse model of AD-like progressive tauopathy. A novel, co-registered in vivo MRI atlas identified particular regions in the medial temporal lobe (MTL) that had significant volume reduction. The medial entorhinal cortex (MEC) and pre-/para-subiculum (PPS) had the most significant atrophy at the early stage, but atrophy then spread into the hippocampus, most notably, the CA1, dentate gyrus (DG) and subiculum (Sub). TBM-related atrophy in the DG and Sub preceded overt cell loss that has been reported in ex vivo studies in the same mouse model. By unifying an ex vivo 3D reconstruction of tau pathology with the TBM-MRI results we mapped the progression of atrophy in the MTL with the corresponding spread of tau pathology. Our study shows that there is an association between the spread of tau pathology and TBM-related atrophy from the EC to the hippocampus, but atrophy in the DG and Sub preceded overt cell loss.One Sentence SummarySpread of tau pathology in a mouse model of Alzheimer’s disease assessed by MRI was associated with reduced brain tissue volume but not neuronal loss.

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