Impact of Anti-amyloid-β Monoclonal Antibodies on the Pathology and Clinical Profile of Alzheimer’s Disease: A Focus on Aducanumab and Lecanemab

Frontiers in Aging Neuroscience, Journal Year: 2022, Volume and Issue: 14

Published: April 12, 2022

Alzheimer's disease (AD) is the most prevalent form of age-related dementia in world, and its main pathological features consist amyloid-β (Aβ) plaque deposits neurofibrillary tangles formed by hyperphosphorylated tau protein. So far, only a few AD treatments approved have been applied clinic, but effects these drugs are limited for partial symptomatic relief to patients with unable alter progression. Later, all efforts targeting pathogenic factors were unsuccessful over past decades, which suggested that pathogenesis complex. Recently, disease-modifying therapies (DMTs) can change underlying pathophysiology AD, anti-Aβ monoclonal antibodies (mabs) (e.g., aducanumab, bapineuzumab, gantenerumab, solanezumab, lecanemab) developed successively conducted clinical trials based on theory systemic failure cell-mediated Aβ clearance contributes occurrence In review, we summarized recent studies therapeutic trial results mabs AD. Specifically, focused discussion impact aducanumab lecanemab pathology profiles. The review provides possible evidence applying immunotherapy analyzes lessons learned from order further study adverse

Language: Английский

---

Forsythoside A Mitigates Alzheimer's-like Pathology by Inhibiting Ferroptosis-mediated Neuroinflammation via Nrf2/GPX4 Axis Activation

International Journal of Biological Sciences, Journal Year: 2022, Volume and Issue: 18(5), P. 2075 - 2090

Published: Jan. 1, 2022

Ferroptosis and neuroinflammation play crucial roles in Alzheimer's disease (AD) pathophysiology. Forsythoside A (FA), the main constituent of Forsythia suspensa (Thunb.) Vahl., possesses anti-inflammatory, antibacterial, antioxidant, neuroprotective properties. The present study aimed to investigate potential role FA AD neuropathology using male APP/PS1 double transgenic mice, Aβ1-42-exposed N2a cells, erastin-stimulated HT22 LPS-induced BV2 cells. treatment significantly improved mitochondrial function inhibited lipid peroxidation In LPS-stimulated decreased formation pro-inflammatory factors IL-6, IL-1β, NO. ameliorated memory cognitive impairments suppressed Aβ deposition p-tau levels brain. Analyses proteomics, immunohistochemistry, ELISA, western blot revealed that augmented dopaminergic signaling, iron peroxidation, prevented activation IKK/IκB/NF-κB reduced secretion factors, promoted production anti-inflammatory exerted anti-ferroptosis anti-neuroinflammatory effects Nrf2/GPX4 axis played a key these effects. Collectively, results demonstrate protective highlight its therapeutic as drug component for treatment.

Language: Английский

---

Lecanemab in patients with early Alzheimer’s disease: detailed results on biomarker, cognitive, and clinical effects from the randomized and open-label extension of the phase 2 proof-of-concept study

Alzheimer s Research & Therapy, Journal Year: 2022, Volume and Issue: 14(1)

Published: Dec. 21, 2022

Abstract Background Lecanemab, a humanized IgG1 monoclonal antibody that targets soluble aggregated Aβ species (protofibrils), has demonstrated robust brain fibrillar amyloid reduction and slowing of clinical decline in early AD. The objective this analysis is to report results from study 201 blinded period (core), the open-label extension (OLE), gap (between core OLE) supporting effectiveness lecanemab. Methods lecanemab was double-blind, randomized, placebo-controlled 856 patients randomized one five dose regimens or placebo. An OLE initiated allow receive 10mg/kg biweekly for up 24 months, with an intervening off-treatment (gap period) ranging 9 59 months (mean months). Results At 12 18 treatment core, 10 mg/kg dose-dependent reductions measured PET corresponding changes plasma biomarkers cognitive decline. rates progression during were similar placebo subjects, differences maintained after discontinued dosing over average period. During gap, Aβ42/40 ratio p-tau181 levels began return towards pre-randomization more quickly than PET. baseline, vs at across 3 assessments. In OLE, produced SUVr, improvements ratio, p-tau181. Conclusions Lecanemab resulted significant plaques Data indicate rapid pronounced correlates benefit potential disease-modifying effects, as well use monitor effects. Trial registration ClinicalTrials.gov NCT01767311 .

Language: Английский

---

Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 23, 2024

Abstract Alzheimer’s disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate diverse, stemming from a combination factors such aging, genetics, environment. Our current understanding AD pathologies involves various hypotheses, cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, abnormal autophagy. Nonetheless, unraveling interplay among these pathological aspects pinpointing primary initiators require further elucidation validation. In past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available primarily offer symptomatic relief often accompanied by undesirable side However, recent approvals aducanumab ( 1 ) lecanemab 2 Food Drug Administration (FDA) present potential in disrease-modifying Nevertheless, long-term efficacy safety need Consequently, quest for safer more effective persists formidable pressing task. This review discusses pathogenesis, advances diagnostic biomarkers, latest updates trials, emerging technologies drug development. We highlight progress discovery selective inhibitors, dual-target allosteric modulators, covalent proteolysis-targeting chimeras (PROTACs), protein-protein interaction (PPI) modulators. goal provide insights into prospective development application novel drugs.

Language: Английский

---

The metal ion hypothesis of Alzheimer’s disease and the anti-neuroinflammatory effect of metal chelators

Bioorganic Chemistry, Journal Year: 2022, Volume and Issue: 131, P. 106301 - 106301

Published: Nov. 25, 2022

Language: Английский

---

Glutamate and GABA in Microglia-Neuron Cross-Talk in Alzheimer’s Disease

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(21), P. 11677 - 11677

Published: Oct. 28, 2021

The physiological balance between excitation and inhibition in the brain is significantly affected Alzheimer's disease (AD). Several neuroactive compounds their signaling pathways through various types of receptors are crucial homeostasis, among them glutamate γ-aminobutyric acid (GABA). Activation microglial regulates immunological response these cells, which AD could be neuroprotective or neurotoxic. novel research approaches revealed complexity function, including interplay with other cells during neuroinflammation brain. purpose this review to describe role several proteins multiple on microglia neurons, involvement a communication network that lead different metabolic loops cell death/survival. Our focused glutamatergic, GABAergic microglia-neuronal cross-talk neuroinflammation. Moreover, significance AD-related neurotoxic glutamate/GABA-mediated dialogue neurons was analyzed search targets neuroprotection, advanced pharmacological approaches.

Language: Английский

---

Lecanemab: First Approval

Drugs, Journal Year: 2023, Volume and Issue: 83(4), P. 359 - 365

Published: March 1, 2023

Language: Английский

---

Current and future therapeutic strategies for Alzheimer’s disease: an overview of drug development bottlenecks

Frontiers in Aging Neuroscience, Journal Year: 2023, Volume and Issue: 15

Published: Aug. 3, 2023

Alzheimer’s disease (AD) is the most common chronic neurodegenerative worldwide. It causes cognitive dysfunction, such as aphasia and agnosia, mental symptoms, behavioral abnormalities; all of which place a significant psychological economic burden on patients’ families. No specific drugs are currently available for treatment AD, current AD only delay onset progression. The pathophysiological basis involves abnormal deposition beta-amyloid protein (Aβ), tau phosphorylation, decreased activity acetylcholine content, glutamate toxicity, autophagy, inflammatory reactions, mitochondria-targeting, multi-targets. US Food Drug Administration (FDA) has approved five clinical use: tacrine, donepezil, carbalatine, galantamine, memantine, lecanemab. We have focused newer that undergone trials, not been successful result excessive side effects or poor efficacy. Although aducanumab received rapid approval from FDA 7 June 2021, its long-term safety tolerability require further monitoring confirmation. In this literature review, we aimed to explore possible mechanisms underlying occurrence development AD. anti-Aβ anti-tau drugs, mitochondria-targeting multi-targets, commercially bottlenecks encountered in drug development, targets therapeutic strategies future development. hope present new concepts methods therapies

Language: Английский

---

Plasma Biomarkers of Alzheimer’s Disease: A Review of Available Assays, Recent Developments, and Implications for Clinical Practice

Journal of Alzheimer s Disease Reports, Journal Year: 2023, Volume and Issue: 7(1), P. 355 - 380

Published: April 25, 2023

Recently, low-sensitive plasma assays have been replaced by new ultra-sensitive such as single molecule enzyme-linked immunosorbent assay (Simoa), the Mesoscale Discovery (MSD) platform, and immunoprecipitation-mass spectrometry (IP-MS) with higher accuracy in determination of biomarkers Alzheimer's disease (AD). Despite significant variability, many studies established in-house cut-off values for most promising available biomarkers. We first reviewed used laboratory methods to measure AD Next, we review focused on diagnostic performance these identify cases, predict cognitive decline pre-clinical differentiate cases from other dementia. summarized data published until January 2023. A combination Aβ42/40 ratio, age, APOE status showed best diagnosing brain amyloidosis a liquid chromatography-mass (LC-MS) assay. Plasma p-tau217 has shown distinguishing Aβ-PET+ Aβ-PET-even cognitively unimpaired individuals. also different each biomarker when available. Recently developed undeniable importance research, improved analytical performance. Some extensively clinical trials are now clinically Nonetheless, several challenges remain their widespread use practice.

Language: Английский

---

Kaempferol, a potential neuroprotective agent in neurodegenerative diseases: From chemistry to medicine

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 165, P. 115215 - 115215

Published: July 24, 2023

Neurodegenerative diseases (NDDs) encompass a range of conditions that involve progressive deterioration and dysfunction the nervous system. Some common NDDs include Alzheimer's disease (AD), Parkinson's (PD), Huntington's (HD), amyotrophic lateral sclerosis (ALS). Although significant progress has been made in understanding pathological mechanisms recent years, development targeted effective drugs for their treatment remains challenging. Kaempferol is flavonoid whose derivatives kaempferol-O-rhamnoside, 3-O-β-rutinoside/6-hydroxykaempferol 3,6-di-O-β-d-glucoside, kaempferide. Emerging studies have suggested kaempferol its possess neuroprotective properties may potential therapeutic benefits NDDs. Here, we aimed to provide theoretical basis use clinical We systematically reviewed literature PubMed, Web Science, Science Direct databases until June 2022 using search terms "kaempferol," "kaempferol derivatives," "NDDs," "pharmacokinetics," "biosynthesis" according reporting items systematic review (PRISMA) standard. Based on combined results vivo vitro studies, summarize basic targets management AD, PD, HD, ALS. exert role mainly by preventing deposition amyloid fibrils (such as Aβ, tau, α-synuclein), inhibiting microglia activation, reducing release inflammatory factors, restoring mitochondrial membrane prevent oxidative stress, protecting blood-brain barrier, specific enzyme activities cholinesterase). are promising natural agents. By determining pharmacological mechanism, be new candidate

Language: Английский

---