Lecanemab‐Associated Amyloid‐β Protofibril in Cerebrospinal Fluid Correlates with Biomarkers of Neurodegeneration in Alzheimer's Disease

Annals of Neurology, Journal Year: 2025, Volume and Issue: 97(5), P. 993 - 1006

Published: Jan. 6, 2025

Objective The Clarity AD phase III trial showed that lecanemab reduced amyloid markers in early Alzheimer's disease (AD) and resulted less decline on measures of cognition function than placebo. Herein, we aimed to characterize amyloid‐β (Aβ) protofibril (PF) captured by human cerebrospinal fluid (CSF) from living participants with different stages AD, which enable an enhanced understanding the dynamic changes lecanemab‐associated Aβ‐PF (Lec‐PF) vivo. Methods We newly developed a unique highly sensitive immunoassay method using selectively captures Lec‐PF. CSF level Lec‐PF, Aβ42, Aβ40, p‐tau181, p‐tau 217, total tau, neurogranin were measured Japanese (n = 163). this study consisted 48 cognitively unimpaired Aβ‐negative (CU–), 8 impaired diagnosed as suspected non‐Alzheimer's pathophysiology, 9 Aβ‐positive (CU+), 34 mild cognitive impairment (MCI+), 64 dementia (AD+). Results Lec‐PF levels significantly increased groups MCI+ AD+ compared CU– group. Notably, modest correlation plaque‐associated biomarkers stronger neurodegeneration biomarkers, such tau neurogranin, suggesting proximally reflect well amount senile plaques. Interpretation This is first report describing species supporting correlated may explain mechanism clinical effect lecanemab. ANN NEUROL 2025;97:993–1006

Language: Английский

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The Mechanisms of the Roles of α-Synuclein, Amyloid-β, and Tau Protein in the Lewy Body Diseases: Pathogenesis, Early Detection, and Therapeutics

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(12), P. 10215 - 10215

Published: June 17, 2023

Lewy body diseases (LBD) are pathologically defined as the accumulation of bodies composed an aggregation α-synuclein (αSyn). In LBD, not only sole αSyn but also co-aggregation amyloidogenic proteins, such amyloid-β (Aβ) and tau, has been reported. this review, pathophysiology αSyn, Aβ, tau protein advancement in imaging fluid biomarkers that can detect co-occurring Aβ and/or pathologies discussed. Additionally, αSyn-targeted disease-modifying therapies clinical trials summarized.

Language: Английский

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ALZ‐801 prevents amyloid β‐protein assembly and reduces cytotoxicity: A preclinical experimental study

The FASEB Journal, Journal Year: 2025, Volume and Issue: 39(3)

Published: Feb. 8, 2025

Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disorder, mainly characterized by amyloid β (Aβ) accumulation in brain. Numerous new agents are currently undergoing clinical trials as disease-modifying therapies (DMTs) targeting Aβ. ALZ-801 a promising candidate DMT for AD, with phase 3 trial of ongoing specifically apolipoprotein E (APOE) ε4 homozygous patients early-stage AD. This study aimed to examine effects on Aβ assembly and explore its toxicological profile. Thioflavin T (ThT) assays two imaging modalities-transmission electron microscopy (TEM) high-speed atomic force (HS-AFM)-were used evaluate ALZ-801's assembly. To assess effect Aβ42-induced cytotoxicity, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) lactate dehydrogenase (LDH) were performed. ThT revealed increased lag time decreased fluorescence presence ALZ-801, confirming inhibition Aβ42 fibril formation, confirmed TEM. Real-time observation using HS-AFM that inhibited formation from low-molecular-weight (LMW)-Aβ42 seeds. also globular aggregates LMW-Aβ42 significantly larger few fibrils noted. MTT LDH indicated prevented LMW-Aβ42-induced cytotoxicity but did not reduce induced high-molecular-weight-Aβ42. can inhibit aggregation preventing both nucleus elongation, while promoting large oligomer cytotoxicity. These findings underscore potential an effective APOE

Language: Английский

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Nano-Scale Video Imaging of Motility Machinery by High-Speed Atomic Force Microscopy

Biomolecules, Journal Year: 2025, Volume and Issue: 15(2), P. 257 - 257

Published: Feb. 10, 2025

Motility is a vital aspect of many forms life, with wide range highly conserved as well unique systems adapted to the needs various organisms and environments. While motility are studied using structural techniques like X-ray crystallography electron microscopy, fluorescence microscopy methodologies, it difficult directly determine relationship between shape movement system due notable gap in spatiotemporal resolution. Bridging this understanding dynamic molecular movements that underpin mechanisms has been challenging. The advent high-speed atomic force (HS-AFM) provided new window into these nano-scale machines processes underlying motility. In review, we highlight some advances field, ranging from reconstituted purified higher-order supramolecular complexes live cells, both prokaryotic eukaryotic contexts.

Language: Английский

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Lecanemab preferentially binds to smaller aggregates present at early Alzheimer's disease

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: 21(4)

Published: April 1, 2025

Abstract INTRODUCTION The monoclonal antibodies Aducanumab, Lecanemab, Gantenerumab, and Donanemab were developed for the treatment of Alzheimer's disease (AD). METHODS We used single‐molecule detection super‐resolution imaging to characterize binding these diffusible amyloid beta (Aβ) aggregates generated in ‐ vitro harvested from human brains. RESULTS Lecanemab showed best performance terms small‐diffusible Aβ aggregates, affinity, aggregate coating, ability bind post‐translationally modified species, providing an explanation its therapeutic success. observed a Braak stage–dependent increase quantity size, which was detectable with Aducanumab but not showing that change progression smaller preferably binds exist at higher quantities during earlier stages. DISCUSSION These findings provide success clinical trials suggests will be more effective when early‐stage AD. Highlights Anti therapeutics are compared by their characteristics. In‐vitro brain‐derived tested using detection. shows formed early disease. high affinity coats them better.

Language: Английский

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The basis of anti-Aβ antibody therapy: The toxicity of Aβ aggregates and the mechanism of action of anti-Aβ antibodies

Internal Medicine, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

In the pathophysiology of Alzheimer's disease (AD), amyloid hypothesis, which posits that β-protein (Aβ) abnormally aggregates and damages neurons with tau, has been proposed. It was originally thought accumulation insoluble fibrils in brain leads to AD-inducing neurotoxicity; however, recent years, positioning early intermediate also emphasized. particular, following positive results phase 3 clinical trials lecanemab its approval Japan United States, pathology protofibrils, are target molecules lecanemab, attracted attention. Using high-speed atomic force microscopy, we have previously reported a high affinity for binds surrounds them. Donanemab, recombinant monoclonal antibody primarily targets composed N3pG Aβ, attention because efficacy patients stage AD.

Language: Английский

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Direct observation of secondary nucleation in huntingtin amyloid formation by High-Speed Atomic Force Microscopy

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 5, 2024

Abstract Amyloid fibril formation is a hallmark of various neurodegenerative diseases such as Huntington’s (HD), Alzheimer’s and Parkinson’s disease. The protein aggregation process involves slow nucleation events followed by rapid growth elongation formed fibrils. Understanding the pathways amyloid key to development novel therapeutic agents that can interfere with pathogenic misfolding events. Recent studies polypeptides from disease have identified importance poorly understood secondary may even be dominant source aggregate formation. Here we focus on polyglutamine-expansion disorder HD employ mechanistic structural study different aspects in huntingtin Exon 1 (HttEx1). Notably, apply high-speed atomic force microscopy (HS-AFM) directly observe single-particle level real time. Our observations show unique features dynamics time, including nucleation, large bundles fibrils result nucleated branching. We examine role HttEx1 flanking segments during process, revealing N-terminal Htt NT segment exhibits clear primary nucleation-aggregation-enhancing ability, however, it does not seem induce or affect process. obtained results illuminate complex implications for attempts inhibit modulate purposes.

Language: Английский

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Neuroprotective Potential of Raloxifene via G-Protein-Coupled Estrogen Receptors in Aβ-Oligomer-Induced Neuronal Injury

Biomedicines, Journal Year: 2023, Volume and Issue: 11(8), P. 2135 - 2135

Published: July 28, 2023

Amyloid-β (Aβ) is one of the causes Alzheimer's disease (AD), damaging nerve membranes and inducing neurotoxicity. AD more prevalent in female patients than male patients, women are susceptible to developing due decline estrogen levels around menopause. Raloxifene, a selective receptor modulator, exhibits protective effects by activating transmembrane G-protein-coupled (GPER). Additionally, raloxifene prevents mild cognitive impairment restores cognition. However, influence via GPER on highly toxic Aβ-oligomers (Aβo)-induced neurotoxicity remains uncertain. In this study, we investigated GPER-mediated neuroprotective against caused Aβo-induced cytotoxicity. The impact cell damage was evaluated using measures such as viability, production reactive oxygen species (ROS) mitochondrial ROS, peroxidation cell-membrane phospholipids, changes intracellular calcium ion concentration ([Ca2+]i) levels. Raloxifene hindered oxidative stress reduced excessive [Ca2+]i, resulting improved viability. Furthermore, these were inhibited with pretreatment antagonist. Our findings suggest that safeguards modifying parameters maintaining [Ca2+]i homeostasis. may prove effective preventing inhibiting progression AD.

Language: Английский

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Distinct Effects of Aducanumab and Lecanemab on Intraneuronal Endogenous Aβ42 and Phosphorylated Tau in Alzheimer’s Disease Treatment

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 6, 2024

Abstract In the treatment of Alzheimer’s Disease (AD), two FDA-approved monoclonal antibodies, Aducanumab (Adu) and Lecanemab (LCN), exhibit significant differences in clinical benefits. By utilizing human-induced basal forebrain cholinergic neurons (BFCNs) derived from AD patient skin fibroblasts, we successfully recapitulated natural endogenous neuropathologies Aβ42 Tau within just 21 days revealed distinct intraneuronal effects Adu LCN. Both antibodies are internalized into BFCNs localize with cytosolic Aβ42. However, LCN, selectively targeting oligomers protofibrils, triggers TRIM21 pathway significantly enhances autolysosome- proteasome-mediated clearance, thereby leading to a marked reduction phosphorylated Tau181 (pTau181) pathology. contrast, fibrillized Aβ42-selective shows considerably weaker effects. This study not only reveals unique actions LCN but also provides reliable accessible human neuronal model for evaluating potential therapeutics, emphasizing importance pathology AD.

Language: Английский

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Anti-amyloid β Antibody Therapies for Alzheimer's Disease: Association between the Target of Amyloid β Aggregates and the Clinical Efficacy of Anti-amyloid β Antibody

Internal Medicine, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Phase 3 clinical trials have validated the efficacy of some anti-amyloid β (Aβ) antibody therapies, such as lecanemab and donanemab. To date, several anti-Aβ drugs been conducted. However, most these methods unsuccessful. Various Aβ aggregates are present during aggregation. The difference in therapy may be attributed to variations targeted. Lecanemab primarily targets protofibrils, donanemab plaques. Solanezumab bapinezumab target monomers alone or from low molecular weight oligomers. Anti-Aβ therapies with cognitive thus characterized by targeting large-molecular-weight aggregates, protofibrils In addition, a positive association was observed between reduction amyloid deposition inhibition decline.

Language: Английский

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