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Introduction: The amyloid cascade hypothesis postulated that the accumulation of amyloid-β (Aβ) was the first step of the Alzheimer's disease (AD) pathological process. Effective reduction of Aβ plaque load by numerous drug candidates, among which anti-Aβ monoclonal antibodies, has produced discussible clinical successes and several failures. It was questioned whether Aβ may be the principal AD pathogenic factor and a valid therapeutic target and if targeting Aβ different species could make the difference., Areas Covered: This review article summarized successes and failures of anti-Aβ monoclonal antibody therapy for AD, delineating the latest advances for their clinical development also according to their target engagement and downstream biomarkers., Expert Opinion: The preliminary success of the recent Phase III randomized clinical trials (RCTs) of lecanemab, donanemab, and remternetug, and lessons learned from the failure of previous anti-Aβ monoclonal antibodies RCTs, provided critical evidence to support the role of Aβ in AD pathogenesis. The loss of free Aβ instead of an Aβ toxicity may promote AD neuropathology. Cerebrospinal fluid analyses (i.e. increases in Aβ 1-42 ) may indicate a potential benefit of anti-Aβ monoclonal antibodies in AD and downstream biomarkers should be considered for providing comprehension in cognitive and clinical efficacy of future AD RCTs.

Magnesium (Mg 2+ ), the second most abundant intracellular cation, plays a crucial role in cellular functions. In this study, we investigate the interaction between Mg 2+ and coenzyme A (CoA), a thiol-containing cofactor central to cellular metabolism also involved in protein modifications. Isothermal titration calorimetry revealed a 1:1 binding stoichiometry between Mg 2+ and free CoA under biologically relevant conditions. Association constants of (537 ± 20) M -1 and (312 ± 7) M -1 were determined at 25 °C and pH 7.2 and 7.8, respectively, suggesting that a significant fraction of CoA is likely bound to Mg 2+ both in the cytosol and in the mitochondrial matrix. Additionally, the process is entropically-driven, and our results support that the origin of the entropy gain is solvent-related. On the other hand, the combination of 1- and 2-dimensional nuclear magnetic resonance spectroscopy with molecular dynamics simulations and unsupervised learning demonstrate a direct coordination between Mg 2+ and the phosphate groups of the 4-phosphopantothenate unit and bound to position 5' of the adenosine ring. Interestingly, the phosphate in position 3' only indirectly contributes to Mg 2+ coordination. Finally, we discuss how the binding of Mg 2+ to CoA perturbates the chemical environment of different CoA atoms, regardless of their apparent proximity to the coordination site, through the modulation of the CoA conformational landscape. This insight holds implications for understanding the impact on both CoA and Mg 2+ functions in physiological and pathological processes., (Copyright © 2024 Elsevier Inc. All rights reserved.)