Publication

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

Bibliographic Details
Summary:	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.
Main Authors:	Fonseca-Gomes, João
Other Authors:	Costa-Coelho, Tiago; Ferreira-Manso, Mafalda; Inteiro-Oliveira, Sara; Vaz, Sandra H.; Alemãn-Serrano, Nuno; Atalaia Barbacena, Henrique; Ribeiro Rodrigues, Leonor; Ramalho, Rita Mira; Climaco Pinto, Rui; Vicente Miranda, Hugo; Tanqueiro, Sara; de Almeida-Borlido, Carolina; Ramalho, Maria João; Miranda-Lourenço, Catarina; Belo, Rita F.; Ferreira, Catarina B.; Neves, Vera; Rombo, Diogo M.; Viais, Ricardo; Umemori, Juzoh; 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; 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
Subject:	Alzheimer’s disease Brain derived neurotrophic factor (BDNF) TAT peptide TAT-TrkB TrkB receptor Amyloid β Drug screening Hippocampal plasticity Learning Memory Protein cleavage.
Year:	2024
Country:	Portugal
Document type:	article
Access type:	open access
Associated institution:	Universidade de Lisboa
Language:	English
Origin:	Repositório da Universidade de Lisboa

Description
Summary:	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.

Funded activities

Loading funded projects...