RESUMEN
Anti-amyloid drugs for early Alzheimer's disease, including lecanemab, are associated with adverse events (AEs), such as amyloid-related imaging abnormalities (ARIA)-edema/effusion (E), ARIA-hemorrhage, and infusion-related reactions, which can indicate allocated arms in clinical trials. Herein, we evaluated the predictive value of AEs using a meta-analysis to estimate their incidence and simulated positive predictive value (PPV). The PPV for ARIA-E was high (0.915), but that for ARIA hemorrhage was low (0.630). Infusion-related reactions had a high PPV of 0.910, but with a wide confidence interval. Our results suggest the need to ameliorate the unblinding effects of AEs, particularly ARIA-E in trials.
RESUMEN
A hallmark of Alzheimer's disease (AD) are the proteinaceous aggregates formed by the amyloid-beta peptide (Aß) that is deposited inside the brain as amyloid plaques. The accumulation of aggregated Aß may initiate or enhance pathologic processes in AD. According to the amyloid hypothesis, any agent that has the capability to inhibit Aß aggregation and/or destroy amyloid plaques represents a potential disease-modifying drug. In 2023, a humanized IgG1 monoclonal antibody (lecanemab) against the Aß-soluble protofibrils was approved by the US FDA for AD therapy, thus providing compelling support to the amyloid hypothesis. To acquire a deeper insight on the in vivo Aß aggregation, various animal models, including aged herbivores and carnivores, non-human primates, transgenic rodents, fish and worms were widely exploited. This review is based on the recent data obtained using transgenic animal AD models and presents experimental verification of the critical role in Aß aggregation seeding of the interactions between zinc ions, Aß with the isomerized Asp7 (isoD7-Aß) and the α4ß2 nicotinic acetylcholine receptor.
Asunto(s)
Enfermedad de Alzheimer , Animales , Enfermedad de Alzheimer/genética , Animales Modificados Genéticamente , Placa Amiloide , Péptidos beta-Amiloides , Proteínas AmiloidogénicasRESUMEN
Amyloids are ubiquitous protein aggregates sharing common internal structural features; they are present in all organisms, from prokaryotes to eukaryotes, where they play physiological or pathological roles. Importantly, amyloids, which are generated by aggregation of a range of distinct proteins, could be a key factor in a number of major human disorders, the so-called conformational diseases. Because all amyloids exhibit similar cross-ß motifs, one may envisage that molecules capable of blocking the formation of ß-sheet structures could abolish aggregation of all amyloid proteins, albeit with different efficacies. Herein, two different ß-sheet blockers were tested against a selection of amyloidogenic proteins, encompassing all the major types of amyloid-based disorders. Analysis of their blocking efficiency, using a simple but contrasted cell-based screening procedure, unequivocally confirms that they indeed behave as aggregation pan-inhibitors. The significant inhibitory effects observed for these compounds against all tested amyloidogenic proteins could spur a broader biological evaluation of other known and new amyloid aggregation inhibitors to further determine the potential use of this class of compounds for the universal treatment of conformational diseases.
Asunto(s)
Amiloide/antagonistas & inhibidores , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/metabolismo , Animales , Descubrimiento de Drogas , Escherichia coli , Humanos , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacología , Fragmentos de Péptidos/química , Fragmentos de Péptidos/metabolismo , Agregación Patológica de Proteínas/tratamiento farmacológico , Estructura Secundaria de Proteína/efectos de los fármacosRESUMEN
We examine the phenomenon of variability in the kinetics of amyloid formation and detail methods for its simulation, identification and analysis. Simulated data, reflecting intrinsic variability, were produced using rate constants, randomly sampled from a pre-defined distribution, as parameters in an irreversible nucleation-growth kinetic model. Simulated kinetic traces were reduced in complexity through description in terms of three characteristic parameters. Practical methods for assessing convergence of the reduced parameter distributions were introduced and a bootstrap procedure was applied to determine convergence for different levels of intrinsic variation. Statistical methods for assessing the significance of shifts in parameter distributions, relating to either change in parameter mean or distribution shape, were tested. Robust methods for analyzing and interpreting kinetic data possessing significant intrinsic variance will allow greater scrutiny of the effects of anti-amyloid compounds in drug trials.
Asunto(s)
Amiloide/química , Simulación por Computador , Modelos Químicos , Agregado de Proteínas , Animales , HumanosRESUMEN
A beta (Aß or ß-amyloid) is a key molecule in Alzheimer's disease (AD) pathogenesis. According to the 'amyloid hypothesis', the gradual accumulation of Aß triggers events which results in neuronal loss in regions of the brain involved with memory and learning. Diverse agents have been developed to reduce brain Aß accumulation or to enhance its clearance. Some have progressed to human trials, however all have failed to improve cognition in patients. This has led researchers to question whether Aß is really the problem. However, the trials have been targeting end stages of AD, by which stage extensive irreversible neuronal damage has already occurred. Intervention is required preclinically, therefore preclinical AD biomarkers are needed. In this regard, amyloid imaging and cerebrospinal fluid biomarkers are leading the way, with plasma biomarkers and eye tests also being investigated. This review covers the current state of knowledge of Aß as an early diagnostic biomarker and as a therapeutic target in AD.