À descoberta dos determinantes estruturais na inibição de interacções proteína-proteína em doenças amilóides neurodegenerativas

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

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

Alzheimer’s disease (AD) is the most common form of dementia around the world (~ 65%). Here, we portray the neuropathology of AD, biomarkers, and classifcation of amyloid plaques (difuse, 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 of-pathways) are described. Aβ42/Aβ40 monomers, dimers, trimers, Aβ‐derived difusible ligands, globulomers, dodecamers, amylospheroids, amorphous aggregates, protofbrils, fbrils, 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.

2024-10-24Journal article

Open access