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Progress toward Alzheimer's disease treatment: Leveraging the Achilles' heel of Aβ oligomers?

Abstract : After three decades of false hopes and failures, a pipeline of therapeutic drugs that target the actual root cause of Alzheimer's disease (AD) is now available. Challenging the old paradigm that focused on β-amyloid peptide (Aβ) aggregation in amyloid plaques, these compounds are designed to prevent the neurotoxicity of Aβ oligomers that form Ca 2+ permeable pores in the membranes of brain cells. By triggering an intracellular Ca 2+ overdose, Aβ oligomers induce a cascade of neurotoxic events including oxidative stress, tau hyperphosphorylation, and neuronal loss. Targeting any post-Ca 2+ entry steps (e.g., tau) will not address the root cause of the disease. Thus, preventing Aβ oligomers formation and/or blocking their toxicity is by essence the best approach to stop any progression of AD. Three categories of anti-oligomer compounds are already available: antibodies, synthetic peptides, and small drugs. Independent in silico-based designs of a peptide (AmyP53) and a mono
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Jacques Fantini, Henri Chahinian, Nouara Yahi. Progress toward Alzheimer's disease treatment: Leveraging the Achilles' heel of Aβ oligomers?. Protein Science, Wiley, 2020, 29, pp.1748 - 1759. ⟨10.1002/pro.3906⟩. ⟨hal-03139186⟩



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