Second-generation anti-amyloid monoclonal antibodies for Alzheimer’s disease: current landscape and future perspectives DOI Creative Commons

Byeong‐Hyeon Kim,

Sujin Kim, Yunkwon Nam

et al.

Translational Neurodegeneration, Journal Year: 2025, Volume and Issue: 14(1)

Published: Jan. 27, 2025

Abstract Alzheimer’s disease (AD) is the most common type of dementia. Monoclonal antibodies (MABs) serve as a promising therapeutic approach for AD by selectively targeting key pathogenic factors, such amyloid-β (Aβ) peptide, tau protein, and neuroinflammation. Specifically, based on their efficacy in removing Aβ plaques from brains patients with AD, U.S. Food Drug Administration has approved three anti-amyloid MABs, aducanumab (Aduhelm®), lecanemab (Leqembi®), donanemab (Kisunla™). Notably, received traditional approval after demonstrating clinical benefit, supporting cascade hypothesis. These MABs are categorized affinity to diverse conformational features Aβ, including monomer, fibril, protofibril, plaque forms well pyroglutamate Aβ. First-generation non-toxic monomeric solanezumab, bapineuzumab, crenezumab, failed demonstrate benefit trials. In contrast, second-generation aducanumab, lecanemab, donanemab, gantenerumab directed against species aggregates have shown that reducing deposition can be an effective strategy slow cognitive impairment AD. this review, we provide comprehensive overview current status, mechanisms, outcomes, limitations treatment Moreover, discuss perspectives future directions

Language: Английский

Adult hippocampal neurogenesis in Alzheimer’s disease: A roadmap to clinical relevance DOI Creative Commons
Evgenia Salta, Orly Lazarov, Carlos P. Fitzsimons

et al.

Cell stem cell, Journal Year: 2023, Volume and Issue: 30(2), P. 120 - 136

Published: Feb. 1, 2023

Adult hippocampal neurogenesis (AHN) drops sharply during early stages of Alzheimer's disease (AD), via unknown mechanisms, and correlates with cognitive status in AD patients. Understanding AHN regulation could provide a framework for innovative pharmacological interventions. We here combine molecular, behavioral, clinical data critically discuss the multicellular complexity niche relation to pathophysiology. further present roadmap toward better understanding role by probing promises caveats latest technological advancements field addressing conceptual methodological challenges ahead.

Language: Английский

Citations

78
Accelerating Alzheimer’s therapeutic development: The past and future of clinical trials DOI Creative Commons
Adam L. Boxer, Reisa A. Sperling

Cell, Journal Year: 2023, Volume and Issue: 186(22), P. 4757 - 4772

Published: Oct. 1, 2023

Alzheimer's disease (AD) research has entered a new era with the recent positive phase 3 clinical trials of anti-Aβ antibodies lecanemab and donanemab. Why did it take 30 years to achieve these successes? Developing potent therapies for reducing fibrillar amyloid was key, as selection patients at relatively early stages disease. Biomarkers target pathologies, including tau PET, insights from past were also critical successes. Moving forward, challenge will be develop more efficacious greater efficiency. Novel trial designs, combination umbrella basket protocols, accelerate development. Better diversity inclusivity participants are needed, blood-based biomarkers may help improve access medically underserved groups. Incentivizing innovation in both academia industry through public-private partnerships, collaborative mechanisms, creation career paths build momentum exciting times.

Language: Английский

Citations

75
Neurovascular coupling mechanisms in health and neurovascular uncoupling in Alzheimer’s disease DOI Creative Commons
Winston M Zhu, Ain Neuhaus, Daniel J. Beard

et al.

Brain, Journal Year: 2022, Volume and Issue: 145(7), P. 2276 - 2292

Published: May 13, 2022

Abstract To match the metabolic demands of brain, mechanisms have evolved to couple neuronal activity vasodilation, thus increasing local cerebral blood flow and delivery oxygen glucose active neurons. Rather than relying on feedback signals such as consumption or glucose, main signalling pathways rely release vasoactive molecules by neurons astrocytes, which act contractile cells. Vascular smooth muscle cells pericytes are associated with arterioles capillaries, respectively, relax induce vasodilation. Much progress has been made in understanding complex neurovascular coupling, but issues contributions capillary astrocyte calcium signal remain contentious. Study coupling is especially important dysregulation a prominent feature Alzheimer’s disease. In this article we will discuss developments controversies finish discussing current knowledge concerning uncoupling

Language: Английский

Citations

70
An anti-amyloid therapy works for Alzheimer’s disease: why has it taken so long and what is next? DOI Creative Commons
John Hardy, Catherine J. Mummery

Brain, Journal Year: 2023, Volume and Issue: 146(4), P. 1240 - 1242

Published: Feb. 17, 2023

Hardy and Mummery discuss the recent positive findings in clinical trial of lecanemab early Alzheimer’s disease, implications for amyloid hypothesis. They argue that results mark a turning point field, but taking anti-amyloid therapies into practice will be challenging.

Language: Английский

Citations

43
Pathological BBB Crossing Melanin-Like Nanoparticles as Metal-Ion Chelators and Neuroinflammation Regulators against Alzheimer’s Disease DOI Creative Commons

Qianqian Huang,

Chaoqing Jiang,

Xue Xia

et al.

Research, Journal Year: 2023, Volume and Issue: 6

Published: Jan. 1, 2023

Inflammatory responses, manifested in excessive oxidative stress and microglia overactivation, together with metal ion-triggered amyloid-beta (Aβ) deposition, are critical hallmarks of Alzheimer’s disease (AD). The intricate pathogenesis causes severe impairment neurons, which, turn, exacerbates Aβ aggregation facilitates AD progression. Herein, multifunctional melanin-like ion chelators neuroinflammation regulators (named PDA@K) were constructed for targeted treatment AD. In this platform, intrinsically bioactive material polydopamine nanoparticles (PDA) potent chelating ROS scavenging effects decorated the KLVFF peptide, endowing system capacity enhanced pathological blood–brain barrier (BBB) crossing lesion site accumulation via hitchhiking. vitro vivo experiment revealed that PDA@K had high affinity toward able to hitch a ride on achieve increased BBB crossing. engineered effectively mitigated aggregate alleviated neuroinflammation. modulated inflammatory microenvironment by promoted microglial polarization M2-like phenotype, which restored their functions neuron care plaque removal. After 3-week PDA@K, spatial learning memory deficit as well neurologic changes FAD 4T transgenic mice largely rescued. Transcriptomics analysis further therapeutic mechanism PDA@K. Our study provided an appealing paradigm directly utilizing intrinsic properties nanomaterials therapeutics instead just using them nanocarriers, widen application therapy.

Language: Английский

Citations

42
Misfolded protein oligomers: mechanisms of formation, cytotoxic effects, and pharmacological approaches against protein misfolding diseases DOI Creative Commons
Dillon J. Rinauro, Fabrizio Chiti, Michele Vendruscolo

et al.

Molecular Neurodegeneration, Journal Year: 2024, Volume and Issue: 19(1)

Published: Feb. 20, 2024

The conversion of native peptides and proteins into amyloid aggregates is a hallmark over 50 human disorders, including Alzheimer's Parkinson's diseases. Increasing evidence implicates misfolded protein oligomers produced during the formation process as primary cytotoxic agents in many these devastating conditions. In this review, we analyze processes by which are formed, their structures, physicochemical properties, population dynamics, mechanisms cytotoxicity. We then focus on drug discovery strategies that target ability to disrupt cell physiology trigger degenerative processes.

Language: Английский

Citations

42
Protein-based bioactive coatings: from nanoarchitectonics to applications DOI
Chengyu Fu,

Zhengge Wang,

Xingyu Zhou

et al.

Chemical Society Reviews, Journal Year: 2024, Volume and Issue: 53(3), P. 1514 - 1551

Published: Jan. 1, 2024

Assembly strategy and application direction of protein-based bioactive coatings.

Language: Английский

Citations

24
Inflammatory aspects of Alzheimer’s disease DOI
Pablo Botella Lucena, Michael T. Heneka

Acta Neuropathologica, Journal Year: 2024, Volume and Issue: 148(1)

Published: Aug. 28, 2024

Language: Английский

Citations

23
Lessons Learned from Approval of Aducanumab for Alzheimer's Disease DOI Creative Commons

Judith L. Heidebrink,

Henry L. Paulson

Annual Review of Medicine, Journal Year: 2024, Volume and Issue: 75(1), P. 99 - 111

Published: Jan. 29, 2024

When the US Food and Drug Administration used accelerated approval process to authorize use of antiamyloid drug aducanumab treat Alzheimer's disease (AD), many people hoped this signaled a new era disease-modifying treatment. But 2 years later, aducanumab's failure launch provides cautionary tale about complexities dementia need for thorough transparent review role that regulatory agencies various stakeholders play in approving AD drugs. We highlight events leading controversial discuss some key lessons learned from drug's deliver hoped-for benefits. These include inherent limitations strategies complex which amyloid is only one several pathological processes, clinical trials better reflect diversity communities affected by AD, potential pitfalls futility analyses trials, greater transparency other modifications process, field's unreadiness move highly controlled environment widespread chronic resource-intensive, drugs real-world treatment scenarios. People with desperately effective therapies. hope story will inspire changes process—changes restore public trust improve future efforts therapies clinic.

Language: Английский

Citations

22
Lipid Peroxidation Drives Liquid–Liquid Phase Separation and Disrupts Raft Protein Partitioning in Biological Membranes DOI Creative Commons
Muthuraj Balakrishnan, Anne K. Kenworthy

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(2), P. 1374 - 1387

Published: Jan. 3, 2024

The peroxidation of membrane lipids by free radicals contributes to aging, numerous diseases, and ferroptosis, an iron-dependent form cell death. Peroxidation changes the structure physicochemical properties lipids, leading bilayer thinning, altered fluidity, increased permeability membranes in model systems. Whether how lipid impacts lateral organization proteins biological membranes, however, remains poorly understood. Here, we employ cell-derived giant plasma vesicles (GPMVs) as a investigate impact on ordered domains, often termed rafts. We show that induced Fenton reaction dramatically enhances phase separation propensity GPMVs into coexisting liquid-ordered (Lo) liquid-disordered (Ld) domains increases relative abundance disordered phase. also leads preferential accumulation peroxidized 4-hydroxynonenal (4-HNE) adducts phase, decreased packing both Lo Ld translocation multiple classes raft out domains. These findings indicate disturbs many aspects rafts, including their stability, abundance, packing, protein composition. propose these disruptions contribute pathological consequences during aging disease thus serve potential targets for therapeutic intervention.

Language: Английский

Citations

21