João Fonseca-Gomes, Tiago Costa-Coelho, Mafalda Ferreira-Manso, Sara Inteiro-Oliveira, Sandra H Vaz, Nuno Alemãn-Serrano, Henrique Atalaia-Barbacena, Leonor Ribeiro-Rodrigues, Rita M Ramalho, Rui Pinto, Hugo Vicente Miranda, Sara R Tanqueiro, Carolina de Almeida-Borlido, Maria João Ramalho, Catarina Miranda-Lourenço, Rita F Belo, Catarina B Ferreira, Vera Neves, Diogo M Rombo, Ricardo Viais, Ivo C Martins, André Jerónimo-Santos, António Caetano, Nuno Manso, Petra Mäkinen, Mikael Marttinen, Mari Takalo, Michael Bremang, Ian Pike, Annakaisa Haapasalo, Joana A Loureiro, Maria Carmo Pereira, Nuno C Santos, Tiago F Outeiro, Miguel A R B Castanho, Adelaide Fernandes, Mikko Hiltunen, Carlos B Duarte, Eero Castrén, Alexandre de Mendonça, Ana M Sebastião, Tiago M Rodrigues, Maria José Diógenes
{"title":"A Small TAT-TrkB Peptide Prevents BDNF Receptor Cleavage and Restores Synaptic Physiology in Alzheimer's Disease.","authors":"João Fonseca-Gomes, Tiago Costa-Coelho, Mafalda Ferreira-Manso, Sara Inteiro-Oliveira, Sandra H Vaz, Nuno Alemãn-Serrano, Henrique Atalaia-Barbacena, Leonor Ribeiro-Rodrigues, Rita M Ramalho, Rui Pinto, Hugo Vicente Miranda, Sara R Tanqueiro, Carolina de Almeida-Borlido, Maria João Ramalho, Catarina Miranda-Lourenço, Rita F Belo, Catarina B Ferreira, Vera Neves, Diogo M Rombo, Ricardo Viais, Ivo C Martins, André Jerónimo-Santos, António Caetano, Nuno Manso, Petra Mäkinen, Mikael Marttinen, Mari Takalo, Michael Bremang, Ian Pike, Annakaisa Haapasalo, Joana A Loureiro, Maria Carmo Pereira, Nuno C Santos, Tiago F Outeiro, Miguel A R B Castanho, Adelaide Fernandes, Mikko Hiltunen, Carlos B Duarte, Eero Castrén, Alexandre de Mendonça, Ana M Sebastião, Tiago M Rodrigues, Maria José Diógenes","doi":"10.1016/j.ymthe.2024.08.022","DOIUrl":null,"url":null,"abstract":"<p><p>In Alzheimer's disease (AD), amyloid β (Aβ)-triggered cleavage of TrkB-FL impairs Brain-derived neurotrophic factor (BDNF) signaling, thereby compromising neuronal survival, differentiation, as well as synaptic transmission and plasticity. Using cerebrospinal fluid and post-mortem human brain samples, we show that TrkB-FL cleavage occurs from the early stages of the disease and increases as function of pathology severity. To explore the therapeutic potential of this disease mechanism, we designed small TAT-fused peptides and screened their ability to prevent TrkB-FL receptor cleavage. Among these, a TAT-TrkB peptide with a lysine-lysine linker prevented TrkB-FL cleavage both in vitro and in vivo and rescued synaptic deficits induced by oligomeric Aβ in hippocampal slices. Furthermore, this TAT-TrkB peptide improved the cognitive performance, ameliorated synaptic plasticity deficits and prevented Tau pathology progression in vivo in the 5XFAD mouse model of AD. No evidence of liver or kidney toxicity was found. We provide proof-of-concept evidence for the efficacy and safety of this therapeutic strategy and anticipate that this TAT-TrkB peptide has the potential of a disease-modifying drug that can prevent and/or reverse cognitive deficits in patients with AD.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":null,"pages":null},"PeriodicalIF":12.1000,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ymthe.2024.08.022","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
In Alzheimer's disease (AD), amyloid β (Aβ)-triggered cleavage of TrkB-FL impairs Brain-derived neurotrophic factor (BDNF) signaling, thereby compromising neuronal survival, differentiation, as well as synaptic transmission and plasticity. Using cerebrospinal fluid and post-mortem human brain samples, we show that TrkB-FL cleavage occurs from the early stages of the disease and increases as function of pathology severity. To explore the therapeutic potential of this disease mechanism, we designed small TAT-fused peptides and screened their ability to prevent TrkB-FL receptor cleavage. Among these, a TAT-TrkB peptide with a lysine-lysine linker prevented TrkB-FL cleavage both in vitro and in vivo and rescued synaptic deficits induced by oligomeric Aβ in hippocampal slices. Furthermore, this TAT-TrkB peptide improved the cognitive performance, ameliorated synaptic plasticity deficits and prevented Tau pathology progression in vivo in the 5XFAD mouse model of AD. No evidence of liver or kidney toxicity was found. We provide proof-of-concept evidence for the efficacy and safety of this therapeutic strategy and anticipate that this TAT-TrkB peptide has the potential of a disease-modifying drug that can prevent and/or reverse cognitive deficits in patients with AD.
在阿尔茨海默病(AD)中,淀粉样蛋白β(Aβ)触发的TrkB-FL裂解会损害脑源性神经营养因子(BDNF)信号传导,从而影响神经元的存活、分化以及突触传递和可塑性。利用脑脊液和死后人脑样本,我们发现TrkB-FL裂解在疾病早期就会发生,并随着病理严重程度的增加而增加。为了探索这一疾病机制的治疗潜力,我们设计了与 TAT 融合的小肽,并筛选了它们阻止 TrkB-FL 受体裂解的能力。其中,一种带有赖氨酸-赖氨酸连接的TAT-TrkB肽在体外和体内都能阻止TrkB-FL的裂解,并能挽救海马片中寡聚Aβ诱导的突触缺陷。此外,这种TAT-TrkB肽还能改善5XFAD小鼠AD模型的认知能力,改善突触可塑性缺陷,防止体内Tau病理学进展。没有发现肝脏或肾脏毒性的证据。我们为这一治疗策略的有效性和安全性提供了概念性证据,并预计这种TAT-TrkB肽有可能成为一种改变疾病的药物,可以预防和/或逆转AD患者的认知障碍。
期刊介绍:
Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.