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 as amyloid-β(Aβ)peptide,ta...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 as amyloid-β(Aβ)peptide,tau protein,and neuroinflammation.Specifically,based on their efficacy in removing Aβplaques from the brains of patients with AD,the U.S.Food and Drug Administration has approved three anti-amyloid MABs,aducanumab(AduhelmR),lecanemab(LeqembiR),and donanemab(Kisunla™).Notably,lecanemab received traditional approval after demonstrating clinical benefit,supporting the Aβcascade hypothesis.These MABs targeting Aβare categorized based on their affinity to diverse conformational features of Aβ,including monomer,fibril,protofibril,and plaque forms of Aβas well as pyroglutamate Aβ.First-generation MABs targeting the non-toxic monomeric Aβ,such as solanezumab,bapineuzumab,and crenezumab,failed to demonstrate clinical benefit for AD in clinical trials.In contrast,secondgeneration MABs,including aducanumab,lecanemab,donanemab,and gantenerumab directed against pathogenic Aβspecies and aggregates have shown that reducing Aβdeposition can be an effective strategy to slow cognitive impairment in AD.In this review,we provide a comprehensive overview of the current status,mechanisms,outcomes,and limitations of second-generation MABs for the clinical treatment of AD.Moreover,we discuss the perspectives and future directions of anti-amyloid MABs in the treatment of AD.展开更多
Alzheimer’s disease(AD)is not a single-cause disease;rather,it is a complex neurodegenerative disease involving multiple pathological pathways influenced by various risk factors.Aggregation and accumulation of amyloi...Alzheimer’s disease(AD)is not a single-cause disease;rather,it is a complex neurodegenerative disease involving multiple pathological pathways influenced by various risk factors.Aggregation and accumulation of amyloid beta(Aβ)and tau are the most prominent features in the brains of AD patients.Aggregated Aβand tau exert neurotoxic effects in the central nervous system,contributing to the pathogenesis and progression of AD.They also act synergistically to cause neurodegeneration,resulting in memory loss.In this context,dual inhibition of Aβand tau aggregation,or dissociation of these two aggregates,is considered promising for AD treatment.Recently,dual inhibitors capable of simultaneously targeting the aggregation and dissociation of both Aβand tau have been investigated.Specific amino acid domains of Aβand tau associated with their aggregation/dissociation have been identified.Subsequently,therapeutic agents that prevent aggregation or promote disaggregation by targeting these domains have been identified/developed.In this review,we summarize the major domains and properties involved in Aβand tau aggregation,as well as the therapeutic effects and mechanisms of agents that simultaneously regulate their aggregation and dissociation.This comprehensive review may contribute to the design and discovery of next-generation dual-targeting drugs for Aβand tau,potentially leading to the development of more effective therapeutic strategies for AD.展开更多
Alzheimer's disease(AD)is the most serious age-related neurodegenerative disease and causes destructive and irreversible cognitive decline.Failures in the development of therapeutics targeting amyloid-β(Aβ)and t...Alzheimer's disease(AD)is the most serious age-related neurodegenerative disease and causes destructive and irreversible cognitive decline.Failures in the development of therapeutics targeting amyloid-β(Aβ)and tau;principal proteins inducing pathology in AD,suggest a paradigm shift towards the development of new therapeutic targets.The gram-negative bacteria and lipopolysaccharides(LPS)are attractive new targets for AD treatment.Surprisingly,an altered distribution of gram-negative bacteria and their LPS has been reported in AD patients.Moreover,gram-negative bacteria and their LPS have been shown to affect a variety of AD-related pathologies,such as Aβ homeostasis,tau pathology,neuroinflammation,and neurodegeneration.Moreover,therapeutic approaches targeting gram-negative bacteria or gram-negative bacterial molecules have significantly alleviated AD-related pathology and cognitive dysfunction.Despite multiple evidence showing that the gram-negative bacteria and their LPS play a crucial role in AD pathogenesis,the pathogenic mechanisms of gram-negative bacteria and their LPS have not been clarified.Here,we summarize the roles and pathomechanisms of gram-negative bacteria and LPS in AD.Furthermore,we discuss the possibility of using gram-negative bacteria and gram-negative bacterial molecules as novel therapeutic targets and new pathological characteristics for AD.展开更多
基金funded by Basic Science Research Program of the National Research Foundation of Korea(NRF)which is funded by the Ministry of Science,ICT&Future Planning(RS-2023–00240010 to M.M.,NRF-2022R1A6A3A13053190 and RS-2024–00450135 to Y.N.,RS-2023–00212388 to S.K.,and RS-2023–00273557 to Y.H.P.)a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute(KHIDI),funded by the Ministry of Health&Welfare,Republic of Korea(RS-2023-KH138733 to M.M.).
文摘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 as amyloid-β(Aβ)peptide,tau protein,and neuroinflammation.Specifically,based on their efficacy in removing Aβplaques from the brains of patients with AD,the U.S.Food and Drug Administration has approved three anti-amyloid MABs,aducanumab(AduhelmR),lecanemab(LeqembiR),and donanemab(Kisunla™).Notably,lecanemab received traditional approval after demonstrating clinical benefit,supporting the Aβcascade hypothesis.These MABs targeting Aβare categorized based on their affinity to diverse conformational features of Aβ,including monomer,fibril,protofibril,and plaque forms of Aβas well as pyroglutamate Aβ.First-generation MABs targeting the non-toxic monomeric Aβ,such as solanezumab,bapineuzumab,and crenezumab,failed to demonstrate clinical benefit for AD in clinical trials.In contrast,secondgeneration MABs,including aducanumab,lecanemab,donanemab,and gantenerumab directed against pathogenic Aβspecies and aggregates have shown that reducing Aβdeposition can be an effective strategy to slow cognitive impairment in AD.In this review,we provide a comprehensive overview of the current status,mechanisms,outcomes,and limitations of second-generation MABs for the clinical treatment of AD.Moreover,we discuss the perspectives and future directions of anti-amyloid MABs in the treatment of AD.
基金funded by the Basic Science Research Program of the National Research Foundation of Korea(NRF)which is funded by the Ministry of Science,ICT&Future Planning(RS-2023-00240010 to M.M.,RS-2024-00450135 to Y.N.and RS-2023-00212388 to S.K.)supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute(KHIDI),funded by the Ministry of Health&Welfare,Republic of Korea(RS-2023-KH138733 to M.M.).
文摘Alzheimer’s disease(AD)is not a single-cause disease;rather,it is a complex neurodegenerative disease involving multiple pathological pathways influenced by various risk factors.Aggregation and accumulation of amyloid beta(Aβ)and tau are the most prominent features in the brains of AD patients.Aggregated Aβand tau exert neurotoxic effects in the central nervous system,contributing to the pathogenesis and progression of AD.They also act synergistically to cause neurodegeneration,resulting in memory loss.In this context,dual inhibition of Aβand tau aggregation,or dissociation of these two aggregates,is considered promising for AD treatment.Recently,dual inhibitors capable of simultaneously targeting the aggregation and dissociation of both Aβand tau have been investigated.Specific amino acid domains of Aβand tau associated with their aggregation/dissociation have been identified.Subsequently,therapeutic agents that prevent aggregation or promote disaggregation by targeting these domains have been identified/developed.In this review,we summarize the major domains and properties involved in Aβand tau aggregation,as well as the therapeutic effects and mechanisms of agents that simultaneously regulate their aggregation and dissociation.This comprehensive review may contribute to the design and discovery of next-generation dual-targeting drugs for Aβand tau,potentially leading to the development of more effective therapeutic strategies for AD.
基金funded by the Basic Science Research Program of the National Research Foundation of Korea(NRF)which is funded by the Ministry of Science,ICT&Future Planning(NRF-2018R1D1A3B07041059 to M.M.and NRF-2016R1A5A2012284 to Y.-M.R)+3 种基金by the Cooperative Research Program for Agriculture Science and Technology Development(Project No.PJ01428603)Rural Development Administration,Republic of Koreaby the Korea Health Technology R&D Project through the Korea Health Industry Development Institute(KHIDI)funded by the Ministry of Health&Welfare,Republic of Korea(grant number:HF21C0021).
文摘Alzheimer's disease(AD)is the most serious age-related neurodegenerative disease and causes destructive and irreversible cognitive decline.Failures in the development of therapeutics targeting amyloid-β(Aβ)and tau;principal proteins inducing pathology in AD,suggest a paradigm shift towards the development of new therapeutic targets.The gram-negative bacteria and lipopolysaccharides(LPS)are attractive new targets for AD treatment.Surprisingly,an altered distribution of gram-negative bacteria and their LPS has been reported in AD patients.Moreover,gram-negative bacteria and their LPS have been shown to affect a variety of AD-related pathologies,such as Aβ homeostasis,tau pathology,neuroinflammation,and neurodegeneration.Moreover,therapeutic approaches targeting gram-negative bacteria or gram-negative bacterial molecules have significantly alleviated AD-related pathology and cognitive dysfunction.Despite multiple evidence showing that the gram-negative bacteria and their LPS play a crucial role in AD pathogenesis,the pathogenic mechanisms of gram-negative bacteria and their LPS have not been clarified.Here,we summarize the roles and pathomechanisms of gram-negative bacteria and LPS in AD.Furthermore,we discuss the possibility of using gram-negative bacteria and gram-negative bacterial molecules as novel therapeutic targets and new pathological characteristics for AD.
