Four-Repeat Tauopathies: Current Management and Future Treatments

VandeVrede, Lawren; Ljubenkov, Peter A.; Rojas, Julio C.; Welch, Ariane E.; Boxer, Adam L.

doi:10.1007/s13311-020-00888-5

Cited by 36 publications

(35 citation statements)

References 197 publications

(161 reference statements)

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“…The repeats, together with their flanking regions, are essential for microtubule binding and, in pathology, influence tangle formation (Delacourte et al, 1996;Chambers et al, 1999;Ishizawa et al, 2000;de Silva et al, 2003;Scheres et al, 2020). Accumulation of 3R and 4R tau isoforms results in distinct clinical manifestations: tangles comprised of paired helical filaments in Alzheimer's disease brain contain a mixture of 3R and 4R tau, whereas 4R isoforms predominate the inclusions in progressive supranuclear palsy and corticobasal degeneration brain (VandeVrede et al, 2020). Pick bodies are predominantly formed of 3R tau isoforms (Goedert and Spillantini, 2019).…”

Section: Introductionmentioning

confidence: 99%

The Disease Associated Tau35 Fragment has an Increased Propensity to Aggregate Compared to Full-Length Tau

Lyu

Vela

Al-Hilaly

et al. 2021

Front. Mol. Biosci.

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Tau35 is a truncated form of tau found in human brain in a subset of tauopathies. Tau35 expression in mice recapitulates key features of human disease, including progressive increase in tau phosphorylation, along with cognitive and motor dysfunction. The appearance of aggregated tau suggests that Tau35 may have structural properties distinct from those of other tau species that could account for its pathological role in disease. To address this hypothesis, we performed a structural characterization of monomeric and aggregated Tau35 and compared the results to those of two longer isoforms, 2N3R and 2N4R tau. We used small angle X-ray scattering to show that Tau35, 2N3R and 2N4R tau all behave as disordered monomeric species but Tau35 exhibits higher rigidity. In the presence of the poly-anion heparin, Tau35 increases thioflavin T fluorescence significantly faster and to a greater extent than full-length tau, demonstrating a higher propensity to aggregate. By using atomic force microscopy, circular dichroism, transmission electron microscopy and X-ray fiber diffraction, we provide evidence that Tau35 aggregation is mechanistically and morphologically similar to previously reported tau fibrils but they are more densely packed. These data increase our understanding of the aggregation inducing properties of clinically relevant tau fragments and their potentially damaging role in the pathogenesis of human tauopathies.

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Section: Introductionmentioning

confidence: 99%

The Disease Associated Tau35 Fragment has an Increased Propensity to Aggregate Compared to Full-Length Tau

Lyu

Vela

Al-Hilaly

et al. 2021

Front. Mol. Biosci.

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“…The results from the UK Biobank cohort will help to inform early diagnosis and stratification of PSP for future disease modifying trials. 27,28…”

Section: Discussionmentioning

confidence: 99%

Prodromal Progressive Supranuclear Palsy – insights from the UK Biobank

Street

Whiteside

Rittman

et al. 2021

Preprint

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Background: Prodromal Parkinsons Disease is well described but prodromal Progressive Supranuclear Palsy (PSP) is much less understood. The diagnosis of PSP is typically delayed by an average of three years after symptom onset. Understanding the changes that occur in the prodromal and prediagnostic period will aid earlier diagnosis, clarify the natural history, and aid the design of early disease modifying therapy trials. Objectives: To determine motor and cognitive markers of prodromal PSP, with Parkinsons disease as a comparator condition, in a large prospective cohort. Methods: Baseline UK Biobank data from 502,504 individuals were collected between 2006 and 2010. Subsequent PSP and Parkinsons disease cases were identified from primary and secondary care electronic health records diagnostic coding data and death registry, with 5,404 matched controls. Results: 176 PSP cases (mean [SD] time to diagnosis 7.8 [2.8] years) and 2,526 Parkinsons disease cases (time to diagnosis 7.8 [2.9] years) were identified. At baseline, those later diagnosed with PSP had slower reaction times, weaker hand grip, lower fluid intelligence, poorer prospective memory, worse self rated health score and lower digit recall than controls. They had higher mortality than both Parkinsons disease and control groups. Conclusions: Motor slowing, cognitive dysfunction, and postural instability are clinical diagnostic features of PSP and are typically symptomatic three years before diagnosis. However, objective markers of these features are evident over seven years before diagnosis. This suggests a long prodromal course in PSP with subtle changes in motor and cognitive function.

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“…Hyper-phosphorylated tau is known as a critical component of AD. In addition, tau is known as a key factor in other diseases, such as tauopathies and glial and neuronal pathologies, and is heterogeneous in various respects, which share many important properties of dementia [ 62 , 63 , 64 ]. For many years, tauopathies were considered of neuronal origin; however, glial cells, astrocytes, and oligodendrocytes, are also involved.…”

Section: Tau and Tauopathiesmentioning

confidence: 99%

Astrocytes: News about Brain Health and Diseases

Meldolesi

2020

Biomedicines

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Astrocytes, the most numerous glial cells in the brains of humans and other mammalian animals, have been studied since their discovery over 100 years ago. For many decades, however, astrocytes were believed to operate as a glue, providing only mechanical and metabolic support to adjacent neurons. Starting from a “revolution” initiated about 25 years ago, numerous astrocyte functions have been reconsidered, some previously unknown, others attributed to neurons or other cell types. The knowledge of astrocytes has been continuously growing during the last few years. Based on these considerations, in the present review, different from single or general overviews, focused on six astrocyte functions, chosen due in their relevance in both brain physiology and pathology. Astrocytes, previously believed to be homogeneous, are now recognized to be heterogeneous, composed by types distinct in structure, distribution, and function; their cooperation with microglia is known to govern local neuroinflammation and brain restoration upon traumatic injuries; and astrocyte senescence is relevant for the development of both health and diseases. Knowledge regarding the role of astrocytes in tauopathies and Alzheimer’s disease has grow considerably. The multiple properties emphasized here, relevant for the present state of astrocytes, will be further developed by ongoing and future studies.

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Four-Repeat Tauopathies: Current Management and Future Treatments

Cited by 36 publications

References 197 publications

The Disease Associated Tau35 Fragment has an Increased Propensity to Aggregate Compared to Full-Length Tau

The Disease Associated Tau35 Fragment has an Increased Propensity to Aggregate Compared to Full-Length Tau

Prodromal Progressive Supranuclear Palsy – insights from the UK Biobank

Astrocytes: News about Brain Health and Diseases

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