A small TAT-TrkB peptide prevents BDNF receptor cleavage and restores synaptic physiology in Alzheimer's disease

• Published in: Molecular therapy Vol. 32; no. 10; p. 3372
• Main Authors: Fonseca-Gomes, João, Costa-Coelho, Tiago, Ferreira-Manso, Mafalda, Inteiro-Oliveira, Sara, Vaz, Sandra H, Alemãn-Serrano, Nuno, Atalaia-Barbacena, Henrique, Ribeiro-Rodrigues, Leonor, Ramalho, Rita M, Pinto, Rui, Vicente Miranda, Hugo, Tanqueiro, Sara R, de Almeida-Borlido, Carolina, Ramalho, Maria João, Miranda-Lourenço, Catarina, Belo, Rita F, Ferreira, Catarina B, Neves, Vera, Rombo, Diogo M, Viais, Ricardo, Martins, Ivo C, Jerónimo-Santos, André, Caetano, António, Manso, Nuno, Mäkinen, Petra, Marttinen, Mikael, Takalo, Mari, Bremang, Michael, Pike, Ian, Haapasalo, Annakaisa, Loureiro, Joana A, Pereira, Maria Carmo, Santos, Nuno C, Outeiro, Tiago F, Castanho, Miguel A R B, Fernandes, Adelaide, Hiltunen, Mikko, Duarte, Carlos B, Castrén, Eero, de Mendonça, Alexandre, Sebastião, Ana M, Rodrigues, Tiago M, Diógenes, Maria José
• Format: Journal Article
• Language: English
• Published: United States 02-10-2024
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Amyloid beta-Peptides - metabolism; Animals; Brain-Derived Neurotrophic Factor - metabolism; Disease Models, Animal; Female; Hippocampus - metabolism; Humans; Male; Membrane Glycoproteins - metabolism; Mice; Mice, Transgenic; Neuronal Plasticity - drug effects; Peptides - pharmacology; Proteolysis - drug effects; Receptor, trkB - metabolism; Synapses - drug effects; Synapses - metabolism; memory; Alzheimer’s disease; BDNF; amyloid β; drug screening; TAT peptide; protein cleavage; learning; TAT-TrkB; TrkB receptor; hippocampal plasticity
• ISSN: 1525-0024
• DOI: 10.1016/j.ymthe.2024.08.022

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.