Tau oligomer induced HMGB1 release contributes to cellular senescence and neuropathology linked to Alzheimer's disease and frontotemporal dementia.
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ABSTRACT:
SUBMITTER: Gaikwad S
PROVIDER: S-EPMC8341760 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:A clinically and pathologically heterogeneous type of frontotemporal lobar degeneration has abnormal tau pathology in neurons and glia (FTLD-tau). Familial FTLD-tau is usually due to mutations in the tau gene (MAPT). Even FTLD-tau determined by MAPT mutations has clinical and pathologic heterogeneity. Tauopathies are subclassified according to the predominant species of tau that accumulates, with respect to alternative splicing of MAPT, with tau proteins containing three (3R) or four repeats (4R) of ~32 amino acids in the microtubule binding domain. In Pick's disease (PiD), 3R tau predominates, whereas 4R tau is characteristic of corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). Depending upon the specific mutation in MAPT, familial FTLD-tau can have 3R, 4R or a combination of 3R and 4R tau. PiD is the least common FTLD-tau characterized by neuronal Pick bodies in a stereotypic neuroanatomical distribution. PSP and CBD are more common than PiD and have extensive clinical and pathologic overlap, with no distinctive clinical syndrome or biomarker that permits their differentiation. Diagnosis rests upon postmortem examination of the brain and demonstration of globose tangles, oligodendroglial coiled bodies and tufted astrocytes in PSP or threads, pretangles and astrocytic plaques in CBD. The anatomical distribution of tau pathology determines the clinical presentation of PSP and CBD, as well as PiD. The basis for this selective cortical vulnerability in FTLD-tau is unknown.
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Project description:Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two incurable neurodegenerative diseases that exist on a clinical, genetic and pathological spectrum. The VCP gene is highly relevant, being directly implicated in both FTD and ALS. Here, we investigate the effects of VCP mutations on the cellular homoeostasis of human induced pluripotent stem cell-derived cortical neurons, focusing on endolysosomal biology and tau pathology. We found that VCP mutations cause abnormal accumulation of enlarged endolysosomes accompanied by impaired interaction between two nuclear RNA binding proteins: fused in sarcoma (FUS) and splicing factor, proline- and glutamine-rich (SFPQ) in human cortical neurons. The spatial dissociation of intranuclear FUS and SFPQ correlates with alternative splicing of the MAPT pre-mRNA and increased tau phosphorylation. Importantly, we show that inducing 4R tau expression using antisense oligonucleotide technology is sufficient to drive neurodegeneration in control human neurons, which phenocopies VCP-mutant neurons. In summary, our findings demonstrate that tau hyperphosphorylation, endolysosomal dysfunction, lysosomal membrane rupture, endoplasmic reticulum stress and apoptosis are driven by a pathogenic increase in 4R tau.
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Project description:Frontotemporal dementia encompasses a group of clinical syndromes defined pathologically by degeneration of the frontal and temporal lobes. Historically, these syndromes have been challenging to diagnose, with an average of about three years between the time of symptom onset and the initial evaluation and diagnosis. Research in the field of neuroimaging has revealed numerous biomarkers of the various frontotemporal dementia syndromes, which has provided clinicians with a method of narrowing the differential diagnosis and improving diagnostic accuracy. As such, neuroimaging is considered a core investigative tool in the evaluation of neurodegenerative disorders. Furthermore, patterns of neurodegeneration correlate with the underlying neuropathological substrates of the frontotemporal dementia syndromes, which can aid clinicians in determining the underlying etiology and improve prognostication. This review explores the advancements in neuroimaging and discusses the phenotypic and pathologic features of behavioral variant frontotemporal dementia, semantic variant primary progressive aphasia, and nonfluent variant primary progressive aphasia, as seen on structural magnetic resonance imaging and positron emission tomography.
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Project description:Antemortem behavioural and anatomic abnormalities have largely been associated with right hemisphere disease in behavioural-variant frontotemporal dementia, but post-mortem neuropathological examination of bilateral hemispheres remains to be defined. Here we measured the severity of post-mortem pathology in both grey and white matter using a validated digital image analysis method in four cortical regions sampled from each hemisphere in 26 patients with behavioural-variant frontotemporal dementia, including those with frontotemporal degeneration (i.e. tau = 9, TDP-43 = 14, or FUS = 1 proteinopathy) or Alzheimer's pathology (n = 2). We calculated an asymmetry index based on the difference in measured pathology from each left-right sample pair. Analysis of the absolute value of the asymmetry index (i.e. degree of asymmetry independent of direction) revealed asymmetric pathology for both grey and white matter in all four regions sampled in frontototemporal degeneration patients with tau or TDP-43 pathology (P ≤ 0.01). Direct interhemispheric comparisons of regional pathology measurements within-subjects in the combined tauopathy and TDP-43 proteinopathy group found higher pathology in the right orbitofrontal grey matter compared to the left (P < 0.01) and increased pathology in ventrolateral temporal lobe grey matter of the left hemisphere compared to the right (P < 0.02). Preliminary group-wise comparisons between tauopathy and TDP-43 proteinopathy groups found differences in patterns of interhemispheric burden of grey and white matter regional pathology, with greater relative white matter pathology in tauopathies. To test the association of pathology measurement with ante-mortem observations, we performed exploratory analyses in the subset of patients with imaging data (n = 15) and found a direct association for increasing pathologic burden with decreasing cortical thickness in frontotemporal regions on ante-mortem imaging in tauopathy (P = 0.001) and a trend for TDP-43 proteinopathy (P = 0.06). Exploratory clinicopathological correlations demonstrated an association of socially-inappropriate behaviours with asymmetric right orbitofrontal grey matter pathology, and reduced semantically-guided category naming fluency was associated asymmetric white matter pathology in the left ventrolateral temporal region. We conclude that pathologic disease burden is distributed asymmetrically in behavioural-variant frontotemporal dementia, although not universally in the right hemisphere, and this asymmetry contributes to the clinical heterogeneity of the disorder. The basis for this asymmetric profile is enigmatic but may reflect distinct species or strains of tau and TDP-43 pathologies with propensities to spread by distinct cell- and region-specific mechanisms. Patterns of region-specific pathology in the right hemisphere as well as the left hemisphere may play a role in antemortem clinical observations, and these observations may contribute to antemortem identification of molecular pathology in frontotemporal degeneration.
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Project description:Exposure to the herbicide paraquat (PQ) is associated with an increased risk of idiopathic Parkinson's disease (PD). Therapies based on PQ's presumed mechanisms of action have not, however, yielded effective disease therapies. Cellular senescence is an anticancer mechanism that arrests proliferation of replication-competent cells and results in a pro-inflammatory senescence-associated secretory phenotype (SASP) capable of damaging neighboring tissues. Here, we demonstrate that senescent cell markers are preferentially present within astrocytes in PD brain tissues. Additionally, PQ was found to induce astrocytic senescence and an SASP in vitro and in vivo, and senescent cell depletion in the latter protects against PQ-induced neuropathology. Our data suggest that exposure to certain environmental toxins promotes accumulation of senescent cells in the aging brain, which can contribute to dopaminergic neurodegeneration. Therapies that target senescent cells may constitute a strategy for treatment of sporadic PD, for which environmental exposure is a major risk factor.
| S-EPMC5806534 | biostudies-literature
Project description:Frontotemporal dementia (FTD) is a frequent form of early-onset dementia and can be caused by mutations in MAPT encoding the microtubule-associated protein tau. Due to limited availability of neural cells from patients` brains, however, the underlying mechanisms of neurodegeneration in FTD are still only poorly understood. Here, we derived induced pluripotent stem (iPS) cells from individuals with FTD-associated MAPT mutations and differentiated them into neurons for mechanistic studies. Patient-derived neurons demonstrated pronounced tau pathology with increased fragmentation and AT8-immunoreactivity, disturbed neurite extension and increased but reversible oxidative stress response to inhibition of mitochondrial respiration. Furthermore, FTD-neurons showed activation of the unfolded protein response and presented with distinct, disease-associated gene expression profiles in a whole-genome transcriptome analysis. These findings indicate distinct, early neurodegenerative changes in FTD caused by mutant tau and highlight the unique opportunity to use patient-specific iPS cells to identify potential targets for drug screening purposes and therapeutic intervention. RNA samples for microarray analysis were prepared using RNeasy columns (Qiagen, Germany) with on-column DNA digestion. 300 ng of total RNA per sample were used as the input in the linear amplification protocol (Ambion), which involved the synthesis of T7-linked double-stranded cDNAs and 12hrs of in vitro transcription incorporating biotin-labeled nucleotides. Purified and labeled cRNA was then hybridized for 18 hrs onto HumanHT-12 v4 expression BeadChips (Illumina, USA) following the manufacturer’s instructions. After the recommended washing, the chips were stained with streptavidin-Cy3 (GE Healthcare) and scanned using the iScan reader (Illumina) and the accompanying software. The samples were exclusively hybridized as biological replicates. The bead intensities were mapped to the corresponding gene information using BeadStudio 3.2 (Illumina) and background correction was performed using the Affymetrix Robust Multi-array Analysis (RMA) background correction model (Irizarry et al., 2003). Variance stabilization was performed using the log2 scaling, and gene expression normalization was calculated with the quantile method implemented in the lumi package of R-Bioconductor. Data post-processing and graphics were performed with in-house developed functions in MATLAB. Hierarchical clusters of genes and samples were performed with the one minus the sample correlation metric and the Unweighted Pair-Group Method using Average (UPGMA) linkage method.
2017-02-10 | GSE62935 | GEO
Project description:Frontotemporal dementia (FTD) is a frequent form of early-onset dementia and can be caused by mutations in MAPT encoding the microtubule-associated protein TAU. Because of limited availability of neural cells from patients' brains, the underlying mechanisms of neurodegeneration in FTD are poorly understood. Here, we derived induced pluripotent stem cells (iPSCs) from individuals with FTD-associated MAPT mutations and differentiated them into mature neurons. Patient iPSC-derived neurons demonstrated pronounced TAU pathology with increased fragmentation and phospho-TAU immunoreactivity, decreased neurite extension, and increased but reversible oxidative stress response to inhibition of mitochondrial respiration. Furthermore, FTD neurons showed an activation of the unfolded protein response, and a transcriptome analysis demonstrated distinct, disease-associated gene expression profiles. These findings indicate distinct neurodegenerative changes in FTD caused by mutant TAU and highlight the unique opportunity to use neurons differentiated from patient-specific iPSCs to identify potential targets for drug screening purposes and therapeutic intervention.
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Project description:Common neurodegenerative diseases feature progressive accumulation of disease-specific protein aggregates in selectively vulnerable brain regions. Increasing experimental evidence suggests that misfolded disease proteins exhibit prion-like properties, including the ability to seed corruptive templating and self-propagation along axons. Direct evidence for transneuronal spread in patients, however, remains limited. To test predictions made by the transneuronal spread hypothesis in human tissues, we asked whether tau deposition within axons of the corticospinal and corticopontine pathways can be predicted based on clinical syndromes and cortical atrophy patterns seen in frontotemporal lobar degeneration (FTLD). Sixteen patients with Pick's disease, 21 with corticobasal degeneration, and 3 with FTLD-MAPT were included, spanning a range of clinical syndromes across the frontotemporal dementia (FTD) spectrum. Cortical involvement was measured using a neurodegeneration score, a tau score, and a composite score based on semiquantitative ratings and complemented by an MRI-based cortical atrophy W-map based on antemortem imaging. Midbrain cerebral peduncle and pontine base descending fibers were divided into three subregions, representing prefrontopontine, corticospinal, and parieto-temporo-occipital fiber pathways. Tau area fraction was calculated in each subregion and related to clinical syndrome and cortical measures. Within each clinical syndrome, there were predicted relationships between cortical atrophy patterns and axonal tau deposition in midbrain cerebral peduncle and pontine base. Between syndromes, contrasting and predictable patterns of brainstem axonal tau deposition emerged, with, for example, greater tau in prefrontopontine fibers in behavioral variant FTD and in corticospinal fibers in corticobasal syndrome. Finally, semiquantitative and quantitative cortical degeneration scores predicted brainstem axonal tau deposition based on anatomical principles. Taken together, these findings provide important human evidence in support of axonal tau spreading in patients with specific forms of tau-related neurodegeneration.
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Project description:Microtubule-associated protein tau mutations result in 10-20% of cases of genetic frontotemporal lobar degeneration. Tau mutation carriers typically develop behavioral variant frontotemporal dementia with or without parkinsonism. Unlike most frontotemporal dementia gene mutations, heterozygous R406W tau mutation carriers most often develop clinical Alzheimer's disease. We report a homozygous tau R406W mutation carrier with behavioral variant frontotemporal dementia who developed symptoms 20 years before mean family symptom onset. Voxel-based morphometry showed frontoinsular, frontal, and mesial temporal cortical atrophy. Homozygous tau R406W mutations appear to accelerate symptom onset and drive a behavioral variant frontotemporal dementia syndrome.
| S-EPMC4693591 | biostudies-literature
Project description:Tau is a microtubule-associated protein that plays an important role in Alzheimer's disease and related tauopathies. Approximately one-half of all cases of Frontotemporal dementia with parkinsonism-17 (FTDP-17) are caused by mutations in the MAPT gene. The N279K mutation is one of the three mutations more prevalent in FTDP-17 cases. Several studies have demonstrated that N279K Tau mutation alters alternative splicing inducing the presence of exon 10. Tau is mainly found in the cytosol of neuronal cells although it has also been localized within the nucleus. Here we demonstrate by biochemical and immunohistochemistry studies in COS-7 cells, that the proportion of mutant N279K Tau increases compared with wild-type at the cell nucleus although cell viability is not affected. These data will provide us with a better outline of the nuclear role of tau protein offering new clues related with this tauopathie.
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