Colocalization of BRCA1 with Tau Aggregates in Human Tauopathies

The mechanism of neuronal dysfunction via tau aggregation in tauopathy patients is controversial. In Alzheimer’s disease (AD), we previously reported mislocalization of the DNA repair nuclear protein BRCA1, its coaggregation with tau, and the possible importance of the subsequent DNA repair dysfunction. However, whether this dysfunction in BRCA1 also occurs in other tauopathies is unknown. The aim of this study was to evaluate whether BRCA1 colocalizes with tau aggregates in the cytoplasm in the brains of the patients with tauopathy. We evaluated four AD, two Pick’s disease (PiD), three progressive supranuclear palsy (PSP), three corticobasal degeneration (CBD), four normal control, and four disease control autopsy brains. Immunohistochemistry was performed using antibodies against BRCA1 and phosphorylated tau (AT8). Colocalization was confirmed by immunofluorescence double staining. Colocalization of BRCA1 with tau aggregates was observed in neurofibrillary tangles and neuropil threads in AD, pick bodies in PiD, and globose neurofibrillary tangles and glial coiled bodies in PSP. However, only partial colocalization was observed in tuft-shaped astrocytes in PSP, and no colocalization was observed in CBD. Mislocalization of BRCA1 was not observed in disease controls. BRCA1 was mislocalized to the cytoplasm and colocalized with tau aggregates in not only AD but also in PiD and PSP. Mislocalization of BRCA1 by tau aggregates may be involved in the pathogenesis of PiD and PSP.

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Aberrant Accumulation of BRCA1 in Alzheimer Disease and Other Tauopathies

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlz107 ◽

2019 ◽

Cited By ~ 4

Author(s):

Masataka Nakamura ◽

Satoshi Kaneko ◽

Dennis W Dickson ◽

Hirofumi Kusaka

Keyword(s):

Alzheimer Disease ◽

Dna Damage Response ◽

Corticobasal Degeneration ◽

The Other ◽

Chromosome 17 ◽

Phosphorylated Tau ◽

Pick Bodies ◽

Neuronal Nuclei ◽

Damage Response ◽

Pick Disease

Abstract BRCA1 plays an important roles in several biological events during the DNA damage response (DDR). Recently, some reports have indicated that BRCA1 dysfunction is involved in the pathogenesis of Alzheimer disease (AD). Furthermore, it has also been reported that BRCA1 accumulates within neurofibrillary tangles (NFTs) in the AD brain. In this study, we examined the immunohistochemical distribution of BRCA1 and another DDR protein, p53-Binding Protein 1 (53BP1), in AD, Pick disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration, and frontotemporal dementia with parkinsonism linked to chromosome 17. In control subjects, neither BRCA1 nor phosphorylated BRCA1 (pBRCA1; Ser1524) immunoreactivity was observed in neurons or glial cells; and that for pBRCA1 (Ser1423) and 53BP1 were slightly detected in neuronal nuclei. The immunoreactivity for both BRCA1 and pBRCA1 (Ser1423) was localized within phosphorylated tau inclusions in all tauopathies, whereas that for pBRCA1 (Ser1524) was mainly associated with Pick bodies in PiD and to a lesser extent with NFTs in AD. On the other hand, 53BP1-immunoreactive deposits tended to be increased in the nucleus of neurons in AD and PSP compared with those in control cases. Our results suggest that DDR dysfunction due to cytoplasmic sequestration of BRCA1 could be involved in the pathogenesis of tauopathies.

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All tangled up: Tau-dependent neurodegeneration

The Biochemist ◽

10.1042/bio03202010 ◽

2010 ◽

Vol 32 (2) ◽

pp. 10-13

Author(s):

Ceri Lyn-Adams ◽

Kevin Moffat ◽

Calum Sutherland ◽

Bruno G. Frenguelli

Keyword(s):

Neurodegenerative Diseases ◽

Progressive Supranuclear Palsy ◽

Neurofibrillary Tangles ◽

Neuronal Loss ◽

Corticobasal Degeneration ◽

Chromosome 17 ◽

Phosphorylated Tau ◽

Brain Correlates ◽

Severity Of Dementia ◽

The Brain

Currently, there are 30 million people worldwide suffering from dementia. This number is predicted to rise to 100 million if effective treatments aren't developed rapidly. Alzheimer's disease (AD) is the most common form of dementia and is also the most prevalent of a group of neurodegenerative diseases known as tauopathies. Tauopathies are characterized by intraneuronal inclusions (pretangles) composed of aggregates of highly phosphorylated tau in the form of paired helical or straight filaments (PHFs), and neuronal loss. As the load of PHFs increases, they will aggregate and eventually form neurofibrillary tangles (NFTs) which fill the whole cell. The number of tau tangles present in the brain correlates well with the severity of dementia. Tau tangles are routinely found in AD, frontotemporal dementia linked to chromosome 17 with parkinsonism (FTDP-17), progressive supranuclear palsy, Pick's disease, corticobasal degeneration, head trauma and Down's syndrome to name but a few.

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Dephosphorylation Passivates the Seeding Activity of Oligomeric Tau Derived From Alzheimer’s Brain

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.631833 ◽

2021 ◽

Vol 14 ◽

Author(s):

Ruozhen Wu ◽

Longfei Li ◽

Ruirui Shi ◽

Yan Zhou ◽

Nana Jin ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurofibrillary Tangles ◽

Cultured Cells ◽

Phosphorylated Tau ◽

Western Blots ◽

Tau Aggregation

Accumulation of intracellular neurofibrillary tangles (NFTs), which are constituted of abnormally phosphorylated tau, is one of the neuropathological hallmarks of Alzheimer’s disease (AD). The oligomeric aggregates of tau in AD brain (AD O-tau) are believed to trigger NFT spreading by seeding normal tau aggregation as toxic seeds, in a prion-like fashion. Here, we revealed the features of AD O-tau by Western blots using antibodies against various epitopes and determined the effect of dephosphorylation on the seeding activity of AD O-tau by capture and seeded aggregation assays. We found that N-terminal truncated and C-terminalhyperphosphorylated tau species were enriched in AD O-tau. Dephosphorylation of AD O-tau by alkaline phosphatasediminished its activity in capturing tau in vitro and ininducing insoluble aggregates in cultured cells. Our resultssuggested that dephosphorylation passivated the seeding activity ofAD O-tau. Inhibition of phosphorylation may be a potentstrategy to prevent the spreading of tau patho3logy.

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Resveratrol Rescues Tau-Induced Cognitive Deficits and Neuropathology in a Mouse Model of Tauopathy

Current Alzheimer Research ◽

10.2174/1567205016666190801153751 ◽

2019 ◽

Vol 16 (8) ◽

pp. 710-722 ◽

Cited By ~ 11

Author(s):

Xiao-Ying Sun ◽

Quan-Xiu Dong ◽

Jie Zhu ◽

Xun Sun ◽

Li-Fan Zhang ◽

...

Keyword(s):

Cognitive Deficits ◽

Therapeutic Potential ◽

Amyloid Β ◽

Synaptic Proteins ◽

Morris Water Maze Test ◽

Phosphorylated Tau ◽

Tau Pathology ◽

Maze Test ◽

N2a Cells ◽

Tau Aggregation

Background: Alzheimer’s Disease (AD) is characterized by the presence of extracellular amyloid-β (Aβ) plaques and intraneuronal neurofibrillary tangles assembled by the microtubuleassociated protein tau. Increasing evidence demonstrated that tau pathology played an important role in AD progression. Resveratrol (RSV) has previously proved to exert neuroprotective effect against AD by inhibiting Aβ generation and Aβ-induced neurocytotoxicity, while its effect on tau pathology is still unknown. Method: The effect of RSV on tau aggregation was measured by Thioflavin T fluorescence and Transmission electron microscope imaging. The effect of RSV on tau oligomer-induced cytotoxicity was assessed by MTT assay and the uptake of extracellular tau by N2a cells was determined by immunocytochemistry. 6-month-old male PS19 mice were treated with RSV or vehicle by oral administration (gavage) once a day for 5 weeks. The cognitive performance was determined using Morris water maze test, object recognition test and Y-maze test. The levels of phosphorylated-tau, gliosis, proinflammatory cytokines such as TNF-α and IL-1β, and synaptic proteins including synaptophysin and PSD95 in the brains of the mice were evaluated by immunoblotting, immunostaining and ELISA, respectively. Results: RSV significantly inhibited tau aggregation and tau oligomer-induced cytotoxicity, and blocked the uptake of extracellular tau oligomers by N2a cells. When applied to PS19 mice, RSV treatment effectively rescued cognitive deficits, reducing the levels of phosphorylated tau, neuroinflammation and synapse loss in the brains of mice. Conclusion: These findings suggest that RSV has promising therapeutic potential for AD and other tauopathies.

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“Don’t Phos Over Tau”: recent developments in clinical biomarkers and therapies targeting tau phosphorylation in Alzheimer’s disease and other tauopathies

Molecular Neurodegeneration ◽

10.1186/s13024-021-00460-5 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Yuxing Xia ◽

Stefan Prokop ◽

Benoit I. Giasson

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Kinase Inhibitors ◽

Tau Phosphorylation ◽

Phosphorylated Tau ◽

Clinical Biomarkers ◽

Early Results ◽

Recent Developments ◽

Tau Aggregation

AbstractPhosphorylation is one of the most prevalent post-translational modifications found in aggregated tau isolated from Alzheimer’s disease (AD) patient brains. In tauopathies like AD, increased phosphorylation or hyperphosphorylation can contribute to microtubule dysfunction and is associated with tau aggregation. In this review, we provide an overview of the structure and functions of tau protein as well as the physiologic roles of tau phosphorylation. We also extensively survey tau phosphorylation sites identified in brain tissue and cerebrospinal fluid from AD patients compared to age-matched healthy controls, which may serve as disease-specific biomarkers. Recently, new assays have been developed to measure minute amounts of specific forms of phosphorylated tau in both cerebrospinal fluid and plasma, which could potentially be useful for aiding clinical diagnosis and monitoring disease progression. Additionally, multiple therapies targeting phosphorylated tau are in various stages of clinical trials including kinase inhibitors, phosphatase activators, and tau immunotherapy. With promising early results, therapies that target phosphorylated tau could be useful at slowing tau hyperphosphorylation and aggregation in AD and other tauopathies.

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Co-factor-free aggregation of tau into seeding-competent RNA-sequestering amyloid fibrils

Nature Communications ◽

10.1038/s41467-021-24362-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Pijush Chakraborty ◽

Gwladys Rivière ◽

Shu Liu ◽

Alain Ibáñez de Opakua ◽

Rıza Dervişoğlu ◽

...

Keyword(s):

Amyloid Fibrils ◽

Corticobasal Degeneration ◽

Binding Studies ◽

Rigid Core ◽

Tau Aggregation ◽

The Brain ◽

Tau Aggregate ◽

Disease Specific ◽

Tau Fibrils

AbstractPathological aggregation of the protein tau into insoluble aggregates is a hallmark of neurodegenerative diseases. The emergence of disease-specific tau aggregate structures termed tau strains, however, remains elusive. Here we show that full-length tau protein can be aggregated in the absence of co-factors into seeding-competent amyloid fibrils that sequester RNA. Using a combination of solid-state NMR spectroscopy and biochemical experiments we demonstrate that the co-factor-free amyloid fibrils of tau have a rigid core that is similar in size and location to the rigid core of tau fibrils purified from the brain of patients with corticobasal degeneration. In addition, we demonstrate that the N-terminal 30 residues of tau are immobilized during fibril formation, in agreement with the presence of an N-terminal epitope that is specifically detected by antibodies in pathological tau. Experiments in vitro and in biosensor cells further established that co-factor-free tau fibrils efficiently seed tau aggregation, while binding studies with different RNAs show that the co-factor-free tau fibrils strongly sequester RNA. Taken together the study provides a critical advance to reveal the molecular factors that guide aggregation towards disease-specific tau strains.

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Tauopathies: A Distinct Class of Neurodegenerative Diseases

Balkan Journal of Medical Genetics ◽

10.2478/v10034-008-0001-5 ◽

2007 ◽

Vol 10 (2) ◽

pp. 3-14 ◽

Cited By ~ 1

Author(s):

M Ozansoy ◽

A Başak

Keyword(s):

Neurodegenerative Diseases ◽

Neurofibrillary Tangles ◽

Neuronal Loss ◽

Corticobasal Degeneration ◽

Chromosome 17 ◽

Cell Degeneration ◽

Distinct Class ◽

Postencephalitic Parkinsonism ◽

Tau Isoforms ◽

Niemann Pick

Tauopathies: A Distinct Class of Neurodegenerative DiseasesNeurodegenerative diseases are characterized by neuronal loss and intraneuronal accumulation of fibrillary materials, of which, neurofibrillary tangles (NFT) are the most common. Neurofibrillary tangles also occur in normal aging and contain the hyperphosphorylated microtubule-associated protein tau. A detailed presentation is made of the molecular bases of Alzheimer's disease (AD), postencephalitic parkinsonism, amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of Guam, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick's disease, frontotemporal dementia (FTD), Down's syndrome, myotonic dystrophy (DM) and Niemann-Pick Type C (NPC) disease, which are considered to be common tauopathies. The unique human tau gene extends over 100 kb of the long arm of chromosome 17 and contains 16 exons. The human brain contains six tau isoforms that contain from 352 to 441 amino acids. To date, 34 pathogenic tau mutations have been described among 101 families affected by FTD with parkinsonism linked to chromosome 17 (FTDP-17). These mutations may involve alternative splicing of exon 10 that lead to changes in the proportion of 4-repeat- and 3-repeat-tau isoforms, or may modify tau interactions with microtubules. Tau aggregates differ in degree of phosphorylation and in content of tau isoforms. Five classes of tauopathies have been defined depending on the type of tau aggregates. The key event in tauopathies is the disorganization of the cytoskeleton, which is based on mutations/polymorphisms in the tau gene and lead to nerve cell degeneration. In this review, tauopathies as a distinct class of neurodegenerative diseases are discussed with emphasis on their molecular pathology and genetics.

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Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease

Science Advances ◽

10.1126/sciadv.aaz2387 ◽

2020 ◽

Vol 6 (16) ◽

pp. eaaz2387 ◽

Cited By ~ 18

Author(s):

Niklas Mattsson-Carlgren ◽

Emelie Andersson ◽

Shorena Janelidze ◽

Rik Ossenkoppele ◽

Philip Insel ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Pet ◽

Phosphorylated Tau ◽

Positron Emission ◽

Aβ Aggregation ◽

Tau Pet ◽

5Xfad Mice ◽

Tau Aggregation ◽

T Tau

The links between β-amyloid (Aβ) and tau in Alzheimer’s disease are unclear. Cognitively unimpaired persons with signs of Aβ pathology had increased cerebrospinal fluid (CSF) phosphorylated tau (P-tau181 and P-tau217) and total-tau (T-tau), which increased over time, despite no detection of insoluble tau aggregates [normal Tau positron emission tomography (PET)]. CSF P-tau and T-tau started to increase before the threshold for Amyloid PET positivity, while Tau PET started to increase after Amyloid PET positivity. Effects of Amyloid PET on Tau PET were mediated by CSF P-tau, and high CSF P-tau predicted increased Tau PET rates. Individuals with MAPT mutations and signs of tau deposition (but without Aβ pathology) had normal CSF P-tau levels. In 5xFAD mice, CSF tau increased when Aβ aggregation started. These results show that Aβ pathology may induce changes in soluble tau release and phosphorylation, which is followed by tau aggregation several years later in humans.

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Efficacy and safety of immunization with phosphorylated tau against neurofibrillary tangles in mice

Experimental Neurology ◽

10.1016/j.expneurol.2010.05.010 ◽

2010 ◽

Vol 224 (2) ◽

pp. 472-485 ◽

Cited By ~ 119

Author(s):

Moran Boimel ◽

Nikolaos Grigoriadis ◽

Athanasios Lourbopoulos ◽

Esther Haber ◽

Oded Abramsky ◽

...

Keyword(s):

Neurofibrillary Tangles ◽

Phosphorylated Tau ◽

Efficacy And Safety

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Coilin Shuttles between the Nucleus and Cytoplasm InXenopus Oocytes

Molecular Biology of the Cell ◽

10.1091/mbc.10.10.3425 ◽

1999 ◽

Vol 10 (10) ◽

pp. 3425-3434 ◽

Cited By ~ 14

Author(s):

Michel Bellini ◽

Joseph G. Gall

Keyword(s):

Nuclear Envelope ◽

Pyruvate Kinase ◽

Western Blotting ◽

Nuclear Import ◽

Nuclear Protein ◽

Germinal Vesicle ◽

Marker Protein ◽

Coiled Bodies ◽

Antibody Complex ◽

Antigen Antibody

Coiled bodies are discrete nuclear organelles often identified by the marker protein p80-coilin. Because coilin is not detected in the cytoplasm by immunofluorescence and Western blotting, it has been considered an exclusively nuclear protein. In theXenopus germinal vesicle (GV), most coilin actually resides in the nucleoplasm, although it is highly concentrated in 50–100 coiled bodies. When affinity-purified anti-coilin antibodies were injected into the cytoplasm of oocytes, they could be detected in coiled bodies within 2–3 h. Coiled bodies were intensely labeled after 18 h, whereas other nuclear organelles remained negative. Because the nuclear envelope does not allow passive diffusion of immunoglobulins, this observation suggests that anti-coilin antibodies are imported into the nucleus as an antigen–antibody complex with coilin. Newly synthesized coilin is not required, because cycloheximide had no effect on nuclear import and subsequent targeting of the antibodies. Additional experiments with myc-tagged coilin and myc-tagged pyruvate kinase confirmed that coilin is a shuttling protein. The shuttling of Nopp140, NO38/B23, and nucleolin was easily demonstrated by the targeting of their respective antibodies to the nucleoli, whereas anti-SC35 did not enter the germinal vesicle. We suggest that coilin, perhaps in association with Nopp140, may function as part of a transport system between the cytoplasm and the coiled bodies.

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