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Article ; Online: Thiophene-Based Ligands: Design, Synthesis and Their Utilization for Optical Assignment of Polymorphic-Disease-Associated Protein Aggregates.

Björk, Linnea / Klingstedt, Therése / Nilsson, K Peter R

Chembiochem : a European journal of chemical biology

2023 Volume 24, Issue 11, Page(s) e202300044

Abstract: The development of ligands for detecting protein aggregates is of great interest, as these aggregated proteinaceous species are the pathological hallmarks of several devastating diseases, including Alzheimer's disease. In this regard, thiophene-based ... ...

Abstract	The development of ligands for detecting protein aggregates is of great interest, as these aggregated proteinaceous species are the pathological hallmarks of several devastating diseases, including Alzheimer's disease. In this regard, thiophene-based ligands have emerged as powerful tools for fluorescent assessment of these pathological entities. The intrinsic conformationally sensitive photophysical properties of poly- and oligothiophenes have allowed optical assignment of disease-associated protein aggregates in tissue sections, as well as real-time in vivo imaging of protein deposits. Herein, we recount the chemical evolution of different generations of thiophene-based ligands, and exemplify their use for the optical distinction of polymorphic protein aggregates. Furthermore, the chemical determinants for achieving a superior fluorescent thiophene-based ligand, as well as the next generation of thiophene-based ligands targeting distinct aggregated species are described. Finally, the directions for future research into the chemical design of thiophene-based ligands that can aid in resolving the scientific challenges around protein aggregation diseases are discussed.
MeSH term(s)	Humans ; Protein Aggregates ; Ligands ; Thiophenes ; Alzheimer Disease/metabolism ; Proteins ; Fluorescent Dyes ; Amyloid beta-Peptides/metabolism
Chemical Substances	Protein Aggregates ; Ligands ; Thiophenes ; Proteins ; Fluorescent Dyes ; Amyloid beta-Peptides
Language	English
Publishing date	2023-05-08
Publishing country	Germany
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2020469-3
ISSN	1439-7633 ; 1439-4227
ISSN (online)	1439-7633
ISSN	1439-4227
DOI	10.1002/cbic.202300044
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Article ; Online: A Novel

Elovsson, Greta / Klingstedt, Therése / Brown, Mikaela / Nilsson, K Peter R / Brorsson, Ann-Christin

International journal of molecular sciences

2024 Volume 25, Issue 4

Abstract: Amyloid-β (Aβ) proteotoxicity is associated with Alzheimer's disease (AD) and is caused by protein aggregation, resulting in neuronal damage in the brain. In the search for novel treatments, ...

Abstract	Amyloid-β (Aβ) proteotoxicity is associated with Alzheimer's disease (AD) and is caused by protein aggregation, resulting in neuronal damage in the brain. In the search for novel treatments,
MeSH term(s)	Animals ; Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Drosophila/metabolism ; Drosophila melanogaster/metabolism ; Amyloid beta-Peptides/genetics ; Gastrointestinal Tract/metabolism ; Disease Models, Animal
Chemical Substances	Amyloid beta-Peptides
Language	English
Publishing date	2024-02-09
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms25042105
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Article ; Online: Thiophene-Based Ligands for Histological Multiplex Spectral Detection of Distinct Protein Aggregates in Alzheimer's Disease.

Lantz, Linda / Shirani, Hamid / Ghetti, Bernardino / Vidal, Ruben / Klingstedt, Therése / Nilsson, K Peter R

Chemistry (Weinheim an der Bergstrasse, Germany)

2023 Volume 29, Issue 21, Page(s) e202203568

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 ... ...

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 Alzheimer's disease (AD). The ability of the ligands to selectively identify AD-associated pathological alterations, such as deposits composed of aggregates of the amyloid-β (Aβ) 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.
MeSH term(s)	Humans ; Alzheimer Disease/metabolism ; Protein Aggregates ; Thiophenes/chemistry ; Ligands ; Amyloid beta-Peptides/chemistry ; Brain/metabolism ; tau Proteins/metabolism
Chemical Substances	Protein Aggregates ; Thiophenes ; Ligands ; Amyloid beta-Peptides ; tau Proteins
Language	English
Publishing date	2023-03-08
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1478547-X
ISSN	1521-3765 ; 0947-6539
ISSN (online)	1521-3765
ISSN	0947-6539
DOI	10.1002/chem.202203568
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Article ; Online: The fluorescent ligand bTVBT2 reveals increased p-tau uptake by retinal microglia in Alzheimer's disease patients and App

Nuñez-Diaz, Cristina / Andersson, Emelie / Schultz, Nina / Pocevičiūtė, Dovilė / Hansson, Oskar / Nilsson, K Peter R / Wennström, Malin

Alzheimer's research & therapy

2024 Volume 16, Issue 1, Page(s) 4

Abstract: Background: Amyloid beta (Aβ) deposits and hyperphosphorylated tau (p-tau) accumulation have been identified in the retina of Alzheimer's disease (AD) patients and transgenic AD mice. Previous studies have shown that retinal microglia engulf Aβ, but ... ...

Abstract	Background: Amyloid beta (Aβ) deposits and hyperphosphorylated tau (p-tau) accumulation have been identified in the retina of Alzheimer's disease (AD) patients and transgenic AD mice. Previous studies have shown that retinal microglia engulf Aβ, but this property decreases in AD patients. Whether retinal microglia also take up p-tau and if this event is affected in AD is yet not described. In the current study, we use the p-tau-specific thiophene-based ligand bTVBT2 to investigate the relationship between disease progression and p-tau uptake by microglia in the retina of AD patients and App Methods: Evaluation of bTVBT2 specificity and its presence within microglia was assessed by immunofluorescent staining of hippocampal sections and flat-mount retina samples from non-demented controls, AD patients, 3-, 9-, and 12-month-old App Results: Confocal imaging analysis showed that bTVBT2 binds to PHF-1- and AT8-positive aggregates inside retinal microglia, and not to Aβ, pTDP-43, or IAPP. The density of bTVBT2-positive microglia was higher in cases with a high Aβ load compared to those with a low Aβ load. This density correlated with the neurofibrillary tangle load in the brain, but not with retinal levels of high molecular weight (aggregated) Aβ40 or Aβ42. Analysis of App Conclusion: Our study suggests that the microglial capability to uptake p-tau in the retina persists and intensifies with AD progression. These results also highlight bTVBT2 as a ligand of interest in future monitoring of retinal AD pathology.
MeSH term(s)	Humans ; Mice ; Animals ; Infant ; Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; Microglia/metabolism ; Ligands ; Mobile Applications ; Mice, Transgenic ; Plaque, Amyloid/pathology ; Disease Models, Animal ; Amyloid beta-Protein Precursor/genetics ; tau Proteins/genetics ; tau Proteins/metabolism
Chemical Substances	Amyloid beta-Peptides ; Ligands ; Amyloid beta-Protein Precursor ; tau Proteins
Language	English
Publishing date	2024-01-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2506521-X
ISSN	1758-9193 ; 1758-9193
ISSN (online)	1758-9193
ISSN	1758-9193
DOI	10.1186/s13195-023-01375-7
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Article ; Online: Thiophene-Based Ligands for Specific Assignment of Distinct Aβ Pathologies in Alzheimer's Disease.

Klingstedt, Therése / Lantz, Linda / Shirani, Hamid / Ge, Junyue / Hanrieder, Jörg / Vidal, Ruben / Ghetti, Bernardino / Nilsson, K Peter R

ACS chemical neuroscience

2024 Volume 15, Issue 7, Page(s) 1581–1595

Abstract: Aggregated species of amyloid-β (Aβ) are one of the pathological hallmarks in Alzheimer's disease (AD), and ligands that selectively target different Aβ deposits are of great interest. In this study, fluorescent thiophene-based ligands have been used to ... ...

Abstract	Aggregated species of amyloid-β (Aβ) are one of the pathological hallmarks in Alzheimer's disease (AD), and ligands that selectively target different Aβ deposits are of great interest. In this study, fluorescent thiophene-based ligands have been used to illustrate the features of different types of Aβ 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
MeSH term(s)	Humans ; Alzheimer Disease/metabolism ; Thiophenes/chemistry ; Ligands ; Amyloid beta-Peptides/metabolism ; Brain/metabolism ; Plaque, Amyloid/metabolism
Chemical Substances	Thiophenes ; Ligands ; Amyloid beta-Peptides
Language	English
Publishing date	2024-03-24
Publishing country	United States
Document type	Journal Article
ISSN	1948-7193
ISSN (online)	1948-7193
DOI	10.1021/acschemneuro.4c00021
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Article: Distinct Heterocyclic Moieties Govern the Selectivity of Thiophene-Vinylene-Based Ligands Towards Aβ or Tau Pathology in Alzheime's Disease.

Björk, Linnea / Shirani, Hamid / Todarwal, Yogesh / Linares, Mathieu / Vidal, Ruben / Ghetti, Bernardino / Norman, Patrick / Klingstedt, Therése / Nilsson, K Peter R

European journal of organic chemistry

2023 Volume 26, Issue 41

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- ... ...

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 Alzheime'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.
Language	English
Publishing date	2023-09-11
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1475010-7
ISSN	1099-0690 ; 1434-193X
ISSN (online)	1099-0690
ISSN	1434-193X
DOI	10.1002/ejoc.202300583
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Article ; Online: Real-time imaging of mitochondrial redox reveals increased mitochondrial oxidative stress associated with amyloid β aggregates in vivo in a mouse model of Alzheimer's disease.

Calvo-Rodriguez, Maria / Kharitonova, Elizabeth K / Snyder, Austin C / Hou, Steven S / Sanchez-Mico, Maria Virtudes / Das, Sudeshna / Fan, Zhanyun / Shirani, Hamid / Nilsson, K Peter R / Serrano-Pozo, Alberto / Bacskai, Brian J

Molecular neurodegeneration

2024 Volume 19, Issue 1, Page(s) 6

Abstract: Background: Reactive oxidative stress is a critical player in the amyloid beta (Aβ) toxicity that contributes to neurodegeneration in Alzheimer's disease (AD). Damaged mitochondria are one of the main sources of reactive oxygen species and accumulate in ...

Abstract	Background: Reactive oxidative stress is a critical player in the amyloid beta (Aβ) toxicity that contributes to neurodegeneration in Alzheimer's disease (AD). Damaged mitochondria are one of the main sources of reactive oxygen species and accumulate in Aβ plaque-associated dystrophic neurites in the AD brain. Although Aβ causes neuronal mitochondria reactive oxidative stress in vitro, this has never been directly observed in vivo in the living mouse brain. Here, we tested for the first time whether Aβ plaques and soluble Aβ oligomers induce mitochondrial oxidative stress in surrounding neurons in vivo, and whether this neurotoxic effect can be abrogated using mitochondrial-targeted antioxidants. Methods: We expressed a genetically encoded fluorescent ratiometric mitochondria-targeted reporter of oxidative stress in mouse models of the disease and performed intravital multiphoton microscopy of neuronal mitochondria and Aβ plaques. Results: For the first time, we demonstrated by direct observation in the living mouse brain exacerbated mitochondrial oxidative stress in neurons after both Aβ plaque deposition and direct application of soluble oligomeric Aβ onto the brain, and determined the most likely pathological sequence of events leading to oxidative stress in vivo. Oxidative stress could be inhibited by both blocking calcium influx into mitochondria and treating with the mitochondria-targeted antioxidant SS31. Remarkably, the latter ameliorated plaque-associated dystrophic neurites without impacting Aβ plaque burden. Conclusions: Considering these results, combination of mitochondria-targeted compounds with other anti-amyloid beta or anti-tau therapies hold promise as neuroprotective drugs for the prevention and/or treatment of AD.
MeSH term(s)	Mice ; Animals ; Amyloid beta-Peptides/metabolism ; Alzheimer Disease/metabolism ; Oxidative Stress/physiology ; Antioxidants/pharmacology ; Antioxidants/metabolism ; Oxidation-Reduction ; Mitochondria/metabolism ; Disease Models, Animal
Chemical Substances	Amyloid beta-Peptides ; Antioxidants
Language	English
Publishing date	2024-01-18
Publishing country	England
Document type	Journal Article
ZDB-ID	2244557-2
ISSN	1750-1326 ; 1750-1326
ISSN (online)	1750-1326
ISSN	1750-1326
DOI	10.1186/s13024-024-00702-2
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Article ; Online: Divergent Age-Dependent Conformational Rearrangement within Aβ Amyloid Deposits in APP23, APPPS1, and

Parvin, Farjana / Haglund, Samuel / Wegenast-Braun, Bettina / Jucker, Mathias / Saito, Takashi / Saido, Takaomi C / Nilsson, K Peter R / Nilsson, Per / Nyström, Sofie / Hammarström, Per

ACS chemical neuroscience

2024

Abstract: Amyloid plaques composed of fibrils of misfolded Aβ peptides are pathological hallmarks of Alzheimer's disease (AD). Aβ fibrils are polymorphic in their tertiary and quaternary molecular structures. This structural polymorphism may carry different ... ...

Abstract	Amyloid plaques composed of fibrils of misfolded Aβ peptides are pathological hallmarks of Alzheimer's disease (AD). Aβ fibrils are polymorphic in their tertiary and quaternary molecular structures. This structural polymorphism may carry different pathologic potencies and can putatively contribute to clinical phenotypes of AD. Therefore, mapping of structural polymorphism of Aβ fibrils and structural evolution over time is valuable to understanding disease mechanisms. Here, we investigated how Aβ fibril structures in situ differ in Aβ plaque of different mouse models expressing familial mutations in the AβPP gene. We imaged frozen brains with a combination of conformation-sensitive luminescent conjugated oligothiophene (LCO) ligands and Aβ-specific antibodies. LCO fluorescence mapping revealed that mouse models APP23, APPPS1, and
Language	English
Publishing date	2024-04-23
Publishing country	United States
Document type	Journal Article
ISSN	1948-7193
ISSN (online)	1948-7193
DOI	10.1021/acschemneuro.4c00104
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Article ; Online: Synthesis and Characterization of Thiophene-based Donor-Acceptor-Donor Heptameric Ligands for Spectral Assignment of Polymorphic Amyloid-β Deposits.

Lantz, Linda / Shirani, Hamid / Klingstedt, Therése / Nilsson, K Peter R

Chemistry (Weinheim an der Bergstrasse, Germany)

2020 Volume 26, Issue 33, Page(s) 7425–7432

Abstract: Protein deposits are associated with many devastating diseases and fluorescent ligands able to visualize these pathological entities are essential. Here, we report the synthesis of thiophene-based donor-acceptor-donor heptameric ligands that can be ... ...

Abstract	Protein deposits are associated with many devastating diseases and fluorescent ligands able to visualize these pathological entities are essential. Here, we report the synthesis of thiophene-based donor-acceptor-donor heptameric ligands that can be utilized for spectral assignment of distinct amyloid-β (Aβ) aggregates, one of the pathological hallmarks in Alzheimer's disease. The ability of the ligands to selectively distinguish Aβ deposits was abolished when the chemical composition of the ligands was altered. Our findings provide the structural and functional basis for the development of new fluorescent ligands that can distinguish between aggregated proteinaceous species consisting of the same peptide or protein. In addition, such ligands might aid in interpreting the potential role of polymorphic Aβ deposits in the pathogenesis of Alzheimer's disease.
MeSH term(s)	Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Amyloid beta-Peptides/chemistry ; Amyloid beta-Peptides/metabolism ; Brain/pathology ; Humans ; Ligands ; Thiophenes/chemical synthesis ; Thiophenes/chemistry
Chemical Substances	Amyloid beta-Peptides ; Ligands ; Thiophenes
Language	English
Publishing date	2020-05-15
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1478547-X
ISSN	1521-3765 ; 0947-6539
ISSN (online)	1521-3765
ISSN	0947-6539
DOI	10.1002/chem.201905612
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Article ; Online: Luminescent-Conjugated Oligothiophene Probe Applications for Fluorescence Imaging of Pure Amyloid Fibrils and Protein Aggregates in Tissues.

Nilsson, K Peter R / Lindgren, Mikael / Hammarström, Per

Methods in molecular biology (Clifton, N.J.)

2018 Volume 1779, Page(s) 485–496

Abstract: Luminescent-conjugated oligo- and polythiophenes (LCOs and LCPs) are valuable tools for optical imaging of a plethora of protein aggregates associated with amyloidoses. Here, we outline updated protocols for the application of the anionic pentameric LCO, ...

Abstract	Luminescent-conjugated oligo- and polythiophenes (LCOs and LCPs) are valuable tools for optical imaging of a plethora of protein aggregates associated with amyloidoses. Here, we outline updated protocols for the application of the anionic pentameric LCO, p-FTAA, for staining and hyperspectral imaging of protein aggregates in a variety of settings such as in vitro formed amyloid fibrils, ex vivo tissue sections, and whole brain Drosophila.
MeSH term(s)	Amyloid/chemistry ; Amyloid/metabolism ; Animals ; Brain/diagnostic imaging ; Brain/metabolism ; Drosophila Proteins/metabolism ; Drosophila melanogaster ; Models, Molecular ; Optical Imaging ; Protein Aggregates ; Protein Multimerization ; Staining and Labeling ; Thiophenes/metabolism
Chemical Substances	Amyloid ; Drosophila Proteins ; Protein Aggregates ; Thiophenes
Language	English
Publishing date	2018-05-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-7816-8_30
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