Transthyretin mutagenesis: impact on amyloidogenesis and disease

Almeida, Zaida L.; Vaz, Daniela C.; Brito, Rui M. M.

doi:10.1080/10408363.2024.2350379

Critical Reviews in Clinical Laboratory Sciences

2024

DOI: 10.1080/10408363.2024.2350379

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Transthyretin mutagenesis: impact on amyloidogenesis and disease

Zaida L. Almeida,

Daniela C. Vaz,

Rui M. M. Brito

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2024

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Cited by 2 publications

References 230 publications

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Morphological and Molecular Profiling of Amyloid-β Species in Alzheimer’s Pathogenesis

Almeida,

Vaz,

Brito

2024

Mol Neurobiol

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Alzheimer’s disease (AD) is the most common form of dementia around the world (~ 65%). Here, we portray the neuropathology of AD, biomarkers, and classification of amyloid plaques (diffuse, non-cored, dense core, compact). Tau pathology and its involvement with Aβ plaques and cell death are discussed. Amyloid cascade hypotheses, aggregation mechanisms, and molecular species formed in vitro and in vivo (on- and off-pathways) are described. Aβ42/Aβ40 monomers, dimers, trimers, Aβ‐derived diffusible ligands, globulomers, dodecamers, amylospheroids, amorphous aggregates, protofibrils, fibrils, and plaques are characterized (structure, size, morphology, solubility, toxicity, mechanistic steps). An update on AD-approved drugs by regulatory agencies, along with new Aβ-based therapies, is presented. Beyond prescribing Aβ plaque disruptors, cholinergic agonists, or NMDA receptor antagonists, other therapeutic strategies (RNAi, glutaminyl cyclase inhibitors, monoclonal antibodies, secretase modulators, Aβ aggregation inhibitors, and anti-amyloid vaccines) are already under clinical trials. New drug discovery approaches based on “designed multiple ligands”, “hybrid molecules”, or “multitarget-directed ligands” are also being put forward and may contribute to tackling this highly debilitating and fatal form of human dementia.

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Morphological and Molecular Profiling of Amyloid-β Species in Alzheimer’s Pathogenesis

Almeida,

Vaz,

Brito

2024

Mol Neurobiol

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A Snapshot of the Most Recent Transthyretin Stabilizers

Marotta,

Ciccone,

Orlandini

et al. 2024

IJMS

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In recent years, several strategies have been developed for the treatment of transthyretin-related amyloidosis, whose complex clinical manifestations involve cardiomyopathy and polyneuropathy. In view of this, transthyretin stabilizers represent a major cornerstone in treatment thanks to the introduction of tafamidis into therapy and the entry of acoramidis into clinical trials. However, the clinical treatment of transthyretin-related amyloidosis still presents several challenges, urging the development of new and improved therapeutics. Bearing this in mind, in this paper, the most promising among the recently published transthyretin stabilizers were reviewed. Their activity was described to provide some insights into their clinical potential, and crystallographic data were provided to explain their modes of action. Finally, structure–activity relationship studies were performed to give some guidance to future researchers aiming to synthesize new transthyretin stabilizers. Interestingly, some new details emerged with respect to the previously known general rules that guided the design of new compounds.

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Transthyretin mutagenesis: impact on amyloidogenesis and disease

Cited by 2 publications

References 230 publications

Morphological and Molecular Profiling of Amyloid-β Species in Alzheimer’s Pathogenesis

Morphological and Molecular Profiling of Amyloid-β Species in Alzheimer’s Pathogenesis

A Snapshot of the Most Recent Transthyretin Stabilizers

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