scholarly journals All tangled up: Tau-dependent neurodegeneration

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.

scholarly journals Tauopathies: A Distinct Class of Neurodegenerative Diseases

2007 ◽  
Vol 10 (2) ◽  
pp. 3-14 ◽  
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.

scholarly journals Mechanisms of Neurodegeneration in Various Forms of Parkinsonism—Similarities and Differences

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 656
Author(s):  
Dariusz Koziorowski ◽  
Monika Figura ◽  
Łukasz M. Milanowski ◽  
Stanisław Szlufik ◽  
Piotr Alster ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Tau Protein ◽  
Protein Gene ◽  
Clinical Presentation ◽  
Neuronal Loss ◽  
Corticobasal Degeneration ◽  
Inflammatory Factors ◽  
Parkinsonian Disorders ◽  
Genetic Features ◽  
The Brain

Parkinson's disease (PD), dementia with Lewy body (DLB), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and multiple system atrophy (MSA) belong to a group of neurodegenerative diseases called parkinsonian syndromes. They share several clinical, neuropathological and genetic features. Neurodegenerative diseases are characterized by the progressive dysfunction of specific populations of neurons, determining clinical presentation. Neuronal loss is associated with extra- and intracellular accumulation of misfolded proteins. The parkinsonian diseases affect distinct areas of the brain. PD and MSA belong to a group of synucleinopathies that are characterized by the presence of fibrillary aggregates of α-synuclein protein in the cytoplasm of selected populations of neurons and glial cells. PSP is a tauopathy associated with the pathological aggregation of the microtubule associated tau protein. Although PD is common in the world's aging population and has been extensively studied, the exact mechanisms of the neurodegeneration are still not fully understood. Growing evidence indicates that parkinsonian disorders to some extent share a genetic background, with two key components identified so far: the microtubule associated tau protein gene (MAPT) and the α-synuclein gene (SNCA). The main pathways of parkinsonian neurodegeneration described in the literature are the protein and mitochondrial pathways. The factors that lead to neurodegeneration are primarily environmental toxins, inflammatory factors, oxidative stress and traumatic brain injury.

scholarly journals Progressive Supranuclear Palsy: A Review of Co-existing Neurodegeneration

2008 ◽  
Vol 35 (5) ◽  
pp. 602-608 ◽  
Author(s):  
J Keith-Rokosh ◽  
L C Ang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Neurodegenerative Diseases ◽  
Progressive Supranuclear Palsy ◽  
Lewy Bodies ◽  
Corticobasal Degeneration ◽  
Pathological Changes ◽  
Subcortical Regions ◽  
Argyrophilic Grains

Objectives:The neuropathological findings of 32 progressive supranuclear palsy (PSP) cases over a period of 17 years were reviewed.Results:Of the 26 cases with adequate clinical data, 20 patients either presented with cognitive dysfunction or developed a cognitive impairment subsequently during the course of the disease. Co-existing changes of argyrophilic grains and corticobasal degeneration (CBD) were found in 28% and 32% of the cases respectively. Alzheimer-related pathology was found in 69% of cases but only 18.75% of cases fulfilled the consortium to establish a registry for Alzheimer's disease (CERAD) criteria for either definite or probable Alzheimer's disease. Lewy bodies were noted in four cases (12.5%), all in the subcortical regions. Only seven cases of PSP showed no pathological evidence of other co-existing neurodegenerative diseases. The severity of the cerebrovascular pathology in this cohort was insufficient to explain any clinical symptomatology.Conclusions:As in previous studies, this study has demonstrated the frequent co-existence of pathological changes usually noted in other neurodegenerative diseases in PSP. Whether these coexisting pathological changes contribute to the cognitive impairment in PSP remains uncertain.

scholarly journals Aberrant Accumulation of BRCA1 in Alzheimer Disease and Other Tauopathies

2019 ◽  
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.

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.

scholarly journals TBK1 interacts with tau and enhances neurodegeneration in tauopathy

2020 ◽  
Author(s):  
Measho H. Abreha ◽  
Shamsideen Ojelade ◽  
Eric B. Dammer ◽  
Zachary T. McEachin ◽  
Duc M. Duong ◽  
...  
Keyword(s):  
Neuronal Loss ◽  
Postmortem Brain ◽  
Chromosome 17 ◽  
Phosphorylation Sites ◽  
Tau Hyperphosphorylation ◽  
Reciprocal Effect ◽  
Full Complement ◽  
The Brain ◽  
Brain Tissues

ABSTRACTOne of the defining pathological features of Alzheimer’s Disease (AD) is the deposition of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau in the brain. Aberrant activation of kinases in AD has been suggested to enhance phosphorylation and toxicity of tau, making the responsible tau-directed kinases attractive therapeutic targets. The full complement of tau interacting kinases in AD brain and their activity in disease remains incompletely defined. Here, immunoaffinity enrichment coupled with mass spectrometry (MS) identified TANK-binding kinase 1 (TBK1) as a tau-interacting partner in human AD cortical brain tissues. We validated this interaction in both human AD and familial frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) caused by mutations in MAPT (R406W) postmortem brain tissues as well as human cell lines. Further, we document increased TBK1 activity in both AD and FTDP-17 and map the predominant TBK1 phosphorylation sites on tau based on in vitro kinase assays coupled to MS. Lastly, in a Drosophila tauopathy model, activating expression of a conserved TBK1 ortholog triggers tau hyperphosphorylation and enhanced neurodegeneration, whereas knockdown had the reciprocal effect, suppressing tau toxicity. Collectively, our findings suggest that increased TBK1 activity may promote tau hyperphosphorylation and neuronal loss in AD and related tauopathies.

scholarly journals Colocalization of BRCA1 with Tau Aggregates in Human Tauopathies

2019 ◽  
Vol 10 (1) ◽  
pp. 7 ◽  
Author(s):  
Masanori Kurihara ◽  
Tatsuo Mano ◽  
Yuko Saito ◽  
Shigeo Murayama ◽  
Tatsushi Toda ◽  
...  
Keyword(s):  
Dna Repair ◽  
Neurofibrillary Tangles ◽  
Nuclear Protein ◽  
Corticobasal Degeneration ◽  
Neuronal Dysfunction ◽  
Phosphorylated Tau ◽  
Double Staining ◽  
Pick Bodies ◽  
Coiled Bodies ◽  
Tau Aggregation

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.

scholarly journals Role of molecular polymorphism in defining tau filament structures in neurodegenerative diseases

2021 ◽  
Author(s):  
Xinyu Xiang ◽  
Tamta Arakhamia ◽  
Yari Carlomagno ◽  
Shikhar Dhingra ◽  
Manon Thierry ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Tau Protein ◽  
Molecular Level ◽  
Corticobasal Degeneration ◽  
Molecular Polymorphism ◽  
Cofactor Binding ◽  
Tau Isoforms ◽  
The Brain ◽  
Disease Specific

Misfolding and aggregation of tau protein is implicated in many neurodegenerative diseases that are typified by the presence of large, filamentous tau inclusions. The aggregation of tau in human brain is disease-specific with characteristic filaments defining the neuropathology. An understanding of how identical tau isoforms aggregate into disparate filament morphologies in phenotypically distinct tau-related diseases remains elusive. Here, we determine the structure of a brain-derived twisted tau filament in progressive supranuclear palsy and compare it to a dissimilar tau fold found in corticobasal degeneration. While the tau filament core in both diseases is comprised of residues 274 to 380, molecular-level polymorphism exists. Potential origins of the molecular polymorphism, such as noncovalent cofactor binding, are identified and predicted to modulate tau filament structures in the brain.

scholarly journals Secernin-1 is a novel phosphorylated tau binding protein that accumulates in Alzheimer’s disease and not in other tauopathies

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Geoffrey Pires ◽  
Sacha McElligott ◽  
Shiron Drusinsky ◽  
Glenda Halliday ◽  
Marie-Claude Potier ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Corticobasal Degeneration ◽  
Amyloid Plaque ◽  
Dystrophic Neurites ◽  
Phosphorylated Tau ◽  
Neuronal Protein ◽  
Age Related ◽  
Late Stages

AbstractWe recently identified Secernin-1 (SCRN1) as a novel amyloid plaque associated protein using localized proteomics. Immunohistochemistry studies confirmed that SCRN1 was present in plaque-associated dystrophic neurites and also revealed distinct and abundant co-localization with neurofibrillary tangles (NFTs). Little is known about the physiological function of SCRN1 and its role in Alzheimer’s disease (AD) and other neurodegenerative diseases has not been studied. Therefore, we performed a comprehensive study of SCRN1 distribution in neurodegenerative diseases. Immunohistochemistry was used to map SCRN1 accumulation throughout the progression of AD in a cohort of 58 patients with a range of NFT pathology (Abundant NFT, n = 21; Moderate NFT, n = 22; Low/No NFT, n = 15), who were clinically diagnosed as having AD, mild cognitive impairment or normal cognition. SCRN1 accumulation was also examined in two cases with both Frontotemporal Lobar Degeneration (FTLD)-Tau and AD-related neuropathology, cases of Down Syndrome (DS) with AD (n = 5), one case of hereditary cerebral hemorrhage with amyloidosis – Dutch type (HCHWA-D) and other non-AD tauopathies including: primary age-related tauopathy (PART, [n = 5]), Corticobasal Degeneration (CBD, [n = 5]), Progressive Supranuclear Palsy (PSP, [n = 5]) and Pick’s disease (PiD, [n = 4]). Immunohistochemistry showed that SCRN1 was a neuronal protein that abundantly accumulated in NFTs and plaque-associated dystrophic neurites throughout the progression of AD. Quantification of SCRN1 immunohistochemistry confirmed that SCRN1 preferentially accumulated in NFTs in comparison to surrounding non-tangle containing neurons at both early and late stages of AD. Similar results were observed in DS with AD and PART. However, SCRN1 did not co-localize with phosphorylated tau inclusions in CBD, PSP or PiD. Co-immunoprecipitation revealed that SCRN1 interacted with phosphorylated tau in human AD brain tissue. Together, these results suggest that SCRN1 is uniquely associated with tau pathology in AD, DS and PART. As such, SCRN1 has potential as a novel therapeutic target and could serve as a useful biomarker to distinguish AD from other tauopathies.

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