| 1. |
- Björk, Linnea, et al.
(författare)
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Distinct Heterocyclic Moieties Govern the Selectivity of Thiophene‐Vinylene‐Based Ligands towards Aβ or Tau Pathology in Alzheimer's Disease
- 2023
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Ingår i: European Journal of Organic Chemistry. - : Wiley. - 1434-193X .- 1099-0690. ; 26:41, s. e202300583-
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Tidskriftsartikel (refereegranskat)abstract
- Distinct aggregated proteins are correlated with numerous neurodegenerative diseases and the development of ligands that selectively detect these pathological hallmarks is vital. Recently, the synthesis of thiophene-based optical ligands, denoted bi-thiophene-vinyl-benzothiazoles (bTVBTs), that could be utilized for selective assignment of tau pathology in brain tissue with Alzheimer's disease (AD) pathology, was reported. Herein, we investigate the ability of these ligands to selectively distinguish tau deposits from aggregated amyloid-β (Aβ), the second AD associated pathological hallmark, when replacing the terminal thiophene moiety with other heterocyclic motifs. The selectivity for tau pathology was reduced when introducing specific heterocyclic motifs, verifying that specific molecular interactions between the ligands and the aggregates are necessary for selective detection of tau deposits. In addition, ligands having certain heterocyclic moieties attached to the central thiophene-vinylene building block displayed selectivity to aggregated Aβ pathology. Our findings provide chemical insights for the development of ligands that can distinguish between aggregated proteinaceous species consisting of different proteins and might also aid in creating novel agents for clinical imaging of tau pathology in AD.
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| 2. |
- Björk, Linnea, et al.
(författare)
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Proteophenes - Amino Acid Functionalized Thiophene-based Fluorescent Ligands for Visualization of Protein Deposits in Tissue Sections with Alzheimers Disease Pathology
- 2022
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Ingår i: Chemistry - A European Journal. - : Wiley-V C H Verlag GMBH. - 0947-6539 .- 1521-3765. ; 28:62
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Tidskriftsartikel (refereegranskat)abstract
- Protein deposits composed of specific proteins or peptides are associated with several neurodegenerative diseases and fluorescent ligands able to detect these pathological hallmarks are vital. Here, we report the synthesis of a class of thiophene-based ligands, denoted proteophenes, with different amino acid side-chain functionalities along the conjugated backbone, which display selectivity towards specific disease-associated protein aggregates in tissue sections with Alzheimers disease (AD) pathology. The selectivity of the ligands towards AD associated pathological hallmarks, such as aggregates of the amyloid-beta (A beta) peptide or tau filamentous inclusions, was highly dependent on the chemical nature of the amino acid functionality, as well as on the location of the functionality along the pentameric thiophene backbone. Finally, the concept of synthesizing donor-acceptor-donor proteophenes with distinct photophysical properties was shown. Our findings provide the structural and functional basis for the development of new thiophene-based ligands that can be utilized for optical assignment of different aggregated proteinaceous species in tissue sections.
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| 3. |
- Gallagher, Michael D., et al.
(författare)
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TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions
- 2014
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 127:3, s. 407-418
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Tidskriftsartikel (refereegranskat)abstract
- Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.
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| 4. |
- Ingelsson, Martin, et al.
(författare)
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Increase in the relative expression of tau with four microtubule binding repeat regions in frontotemporal lobar degeneration and progressive supranuclear palsy brains
- 2007
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 114:5, s. 471-479
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Tidskriftsartikel (refereegranskat)abstract
- Some cases of familial frontotemporal dementia (FTD) leading to frontotemporal lobar degeneration (FTLD) are caused by mutations in tau on chromosome 17 (FTDP-17). Certain mutations alter the ratio between four (4R tau) and three (3R tau) repeat tau isoforms whereas cases with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) mainly have 4R tau brain pathology. We assessed tau mRNA and protein levels in frontal cortex from 15 sporadic FTLD, 21 PSP, 5 CBD, 15 Alzheimer’s disease (AD) and 16 control brains. Moreover, we investigated the disease association and possible tau splicing effects of the tau H1 haplotype. Cases with FTLD and PSP had lower tau mRNA levels than control brains. When analyzing 4R tau and 3R tau mRNA separately, control subjects displayed a 4R tau/3R tau ratio of 0.48. Surprisingly, FTLD brains displayed a more elevated ratio (1.32) than PSP brains (1.12). Also, several FTLD and PSP cases had higher 4R tau/3R tau mRNA than FTDP-17 cases, included as reference tissues, and the ratio increase was seen regardless of underlying histopathology, i.e. both for tau-positive and tau-negative FTLD cases. Furthermore, total tau protein levels were slightly decreased in both FTLD and AD as compared to control subjects. Finally, we confirmed the association of tau H1 with PSP, but could not find any haplotype-related effect on tau exon 10 splicing. In conclusion, we demonstrated increased but largely variable 4R tau/3R tau mRNA ratios in FTLD and PSP cases, suggesting heterogeneous pathophysiological processes within these disorders.
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| 5. |
- Klingstedt, Therése, et al.
(författare)
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Luminescent conjugated oligothiophenes distinguish between alpha-synuclein assemblies of Parkinsons disease and multiple system atrophy
- 2019
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Ingår i: Acta neuropathologica communications. - : BMC. - 2051-5960. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Synucleinopathies [Parkinsons disease with or without dementia, dementia with Lewy bodies and multiple system atrophy] are neurodegenerative diseases that are defined by the presence of filamentous alpha-synuclein inclusions. We investigated the ability of luminescent conjugated oligothiophenes to stain the inclusions of Parkinsons disease and multiple system atrophy. They stained the Lewy pathology of Parkinsons disease and the glial cytoplasmic inclusions of multiple system atrophy. Spectral analysis of HS-68-stained inclusions showed a red shift in multiple system atrophy, but the difference with Parkinsons disease was not significant. However, when inclusions were double-labelled for HS-68 and an antibody specific for alpha-synuclein phosphorylated at S129, they could be distinguished based on colour shifts with blue designated for Parkinsons disease and red for multiple system atrophy. The inclusions of Parkinsons disease and multiple system atrophy could also be distinguished using fluorescence lifetime imaging. These findings are consistent with the presence of distinct conformers of assembled a-synuclein in Parkinsons disease and multiple system atrophy.
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| 6. |
- Klingstedt, Therése, et al.
(författare)
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Thiophene-Based Ligands for Specific Assignment of Distinct Aß Pathologies in Alzheimer's Disease
- 2024
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Ingår i: ACS Chemical Neuroscience. - : AMER CHEMICAL SOC. - 1948-7193.
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Tidskriftsartikel (refereegranskat)abstract
- Aggregated species of amyloid-beta (A beta) are one of the pathological hallmarks in Alzheimer's disease (AD), and ligands that selectively target different A beta deposits are of great interest. In this study, fluorescent thiophene-based ligands have been used to illustrate the features of different types of A beta deposits found in AD brain tissue. A dual-staining protocol based on two ligands, HS-276 and LL-1, with different photophysical and binding properties, was developed and applied on brain tissue sections from patients affected by sporadic AD or familial AD associated with the PSEN1 A431E mutation. When binding to A beta deposits, the ligands could easily be distinguished for their different fluorescence, and distinct staining patterns were revealed for these two types of AD. In sporadic AD, HS-276 consistently labeled all immunopositive A beta plaques, whereas LL-1 mainly stained cored and neuritic A beta deposits. In the PSEN1 A431E cases, each ligand was binding to specific types of A beta plaques. The ligand-labeled A beta deposits were localized in distinct cortical layers, and a laminar staining pattern could be seen. Biochemical characterization of the A beta aggregates in the individual layers also showed that the variation of ligand binding properties was associated with certain A beta peptide signatures. For the PSEN1 A431E cases, it was concluded that LL-1 was binding to cotton wool plaques, whereas HS-276 mainly stained diffuse A beta deposits. Overall, our findings showed that a combination of ligands was essential to identify distinct aggregated A beta species associated with different forms of AD.
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| 7. |
- Klingstedt, Therése, et al.
(författare)
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Thiophene-Based Ligands for Specific Assignment of Distinct Aβ Pathologies in Alzheimer's Disease
- 2024
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Ingår i: ACS CHEMICAL NEUROSCIENCE. - : AMER CHEMICAL SOC. - 1948-7193. ; 15:7, s. 1581-1595
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Tidskriftsartikel (refereegranskat)abstract
- Aggregated species of amyloid-beta (A beta) are one of the pathological hallmarks in Alzheimer's disease (AD), and ligands that selectively target different A beta deposits are of great interest. In this study, fluorescent thiophene-based ligands have been used to illustrate the features of different types of A beta deposits found in AD brain tissue. A dual-staining protocol based on two ligands, HS-276 and LL-1, with different photophysical and binding properties, was developed and applied on brain tissue sections from patients affected by sporadic AD or familial AD associated with the PSEN1 A431E mutation. When binding to A beta deposits, the ligands could easily be distinguished for their different fluorescence, and distinct staining patterns were revealed for these two types of AD. In sporadic AD, HS-276 consistently labeled all immunopositive A beta plaques, whereas LL-1 mainly stained cored and neuritic A beta deposits. In the PSEN1 A431E cases, each ligand was binding to specific types of A beta plaques. The ligand-labeled A beta deposits were localized in distinct cortical layers, and a laminar staining pattern could be seen. Biochemical characterization of the A beta aggregates in the individual layers also showed that the variation of ligand binding properties was associated with certain A beta peptide signatures. For the PSEN1 A431E cases, it was concluded that LL-1 was binding to cotton wool plaques, whereas HS-276 mainly stained diffuse A beta deposits. Overall, our findings showed that a combination of ligands was essential to identify distinct aggregated A beta species associated with different forms of AD.
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| 8. |
- Klingstedt, Therése, et al.
(författare)
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Thiophene-Based Optical Ligands That Selectively Detect A beta Pathology in Alzheimers Disease
- 2021
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Ingår i: ChemBioChem. - : Wiley-V C H Verlag GMBH. - 1439-4227 .- 1439-7633. ; 22:15, s. 2568-2581
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Tidskriftsartikel (refereegranskat)abstract
- In several neurodegenerative diseases, the presence of aggregates of specific proteins in the brain is a significant pathological hallmark; thus, developing ligands able to bind to the aggregated proteins is essential for any effort related to imaging and therapeutics. Here we report the synthesis of thiophene-based ligands containing nitrogen heterocycles. The ligands selectively recognized amyloid-beta (A beta) aggregates in brain tissue from individuals diagnosed neuropathologically as having Alzheimers disease (AD). The selectivity for A beta was dependent on the position of nitrogen in the heterocyclic compounds, and the ability to bind A beta was shown to be reduced when introducing anionic substituents on the thiophene backbone. Our findings provide the structural and functional basis for the development of ligands that can differentiate between aggregated proteinaceous species comprised of distinct proteins. These ligands might also be powerful tools for studying the pathogenesis of A beta aggregation and for designing molecules for imaging of A beta pathology.
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| 9. |
- Kovacs, Gabor G., et al.
(författare)
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Aging-related tau astrogliopathy (ARTAG) : harmonized evaluation strategy
- 2016
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 131:1, s. 87-102
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Tidskriftsartikel (refereegranskat)abstract
- Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or granular immunopositivity, typically in gray matter. Various forms of ARTAG may coexist in the same brain and might reflect different pathogenic processes. Based on morphology and anatomical distribution, ARTAG can be distinguished from primary tauopathies, but may be concurrent with primary tauopathies or other disorders. We recommend four steps for evaluation of ARTAG: (1) identification of five types based on the location of either morphologies of tau astrogliopathy: subpial, subependymal, perivascular, white matter, gray matter; (2) documentation of the regional involvement: medial temporal lobe, lobar (frontal, parietal, occipital, lateral temporal), subcortical, brainstem; (3) documentation of the severity of tau astrogliopathy; and (4) description of subregional involvement. Some types of ARTAG may underlie neurological symptoms; however, the clinical significance of ARTAG is currently uncertain and awaits further studies. The goal of this proposal is to raise awareness of astroglial tau pathology in the aged brain, facilitating communication among neuropathologists and researchers, and informing interpretation of clinical biomarkers and imaging studies that focus on tau-related indicators.
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| 10. |
- Lantz, Linda, et al.
(författare)
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Thiophene-Based Ligands for Histological Multiplex Spectral Detection of Distinct Protein Aggregates in Alzheimers Disease
- 2023
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Ingår i: Chemistry - A European Journal. - : WILEY-V C H VERLAG GMBH. - 0947-6539 .- 1521-3765.
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Tidskriftsartikel (refereegranskat)abstract
- The aggregation and accumulation of proteins in the brain is the defining feature of many devastating neurodegenerative diseases. The development of fluorescent ligands that bind to these accumulations, or deposits, is essential for the characterization of these neuropathological lesions. We report the synthesis of donor-acceptor-donor (D-A-D) thiophene-based ligands with different emission properties. The D-A-D ligands displayed selectivity towards distinct disease-associated protein deposits in histological sections from postmortem brain tissue of individuals affected by Alzheimers disease (AD). The ability of the ligands to selectively identify AD-associated pathological alterations, such as deposits composed of aggregates of the amyloid-beta (A beta) peptide or tau, was reduced when the chemical composition of the ligands was altered. When combining the D-A-D ligands with conventional thiophene-based ligands, superior spectral separation of distinct protein aggregates in AD tissue sections was obtained. Our findings provide the structural and functional basis for the development of new fluorescent ligands that can distinguish between aggregated proteinaceous species, as well as offer novel strategies for developing multiplex fluorescence detection of protein aggregates in tissue sections.
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