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A Small TAT-TrkB Peptide Prevents BDNF Receptor Cleavage and Restores Synaptic Physiology in Alzheimer’s Disease

2024; Elsevier BV; Volume: 32; Issue: 10 Linguagem: Inglês

10.1016/j.ymthe.2024.08.022

1525-0024

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, Juzoh Umemori, 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 do Carmo Pereira, Nuno C. Santos, Tiago F. Outeiro, Miguel A. R. B. Castanho, Adelaide Fernandes, Mikko Hiltunen, Carlos B. Duarte, Eero Ċastrén, Alexandre de Mendonça, Ana M. Sebastião, Tiago M. Rodrigues, Maria José Diógenes,

Alzheimer's disease research and treatments

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, and synaptic transmission and plasticity. Using cerebrospinal fluid and postmortem human brain samples, we show that TrkB-FL cleavage occurs from the early stages of the disease and increases as a 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 to be a disease-modifying drug that can prevent and/or reverse cognitive deficits in patients with AD.Graphical abstract