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. 2024 Oct 2;32(10):3372-3401.
doi: 10.1016/j.ymthe.2024.08.022. Epub 2024 Aug 27.

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

João Fonseca-Gomes  1 , Tiago Costa-Coelho  2 , Mafalda Ferreira-Manso  3 , Sara Inteiro-Oliveira  1 , Sandra H Vaz  1 , Nuno Alemãn-Serrano  1 , Henrique Atalaia-Barbacena  1 , Leonor Ribeiro-Rodrigues  1 , Rita M Ramalho  1 , Rui Pinto  4 , Hugo Vicente Miranda  5 , Sara R Tanqueiro  1 , Carolina de Almeida-Borlido  1 , Maria João Ramalho  6 , Catarina Miranda-Lourenço  1 , Rita F Belo  1 , Catarina B Ferreira  1 , Vera Neves  7 , Diogo M Rombo  1 , Ricardo Viais  1 , Juzoh Umemori  8 , Ivo C Martins  7 , André Jerónimo-Santos  1 , António Caetano  1 , Nuno Manso  9 , Petra Mäkinen  10 , Mikael Marttinen  11 , Mari Takalo  10 , Michael Bremang  12 , Ian Pike  12 , Annakaisa Haapasalo  13 , Joana A Loureiro  6 , Maria Carmo Pereira  6 , Nuno C Santos  7 , Tiago F Outeiro  14 , Miguel A R B Castanho  7 , Adelaide Fernandes  15 , Mikko Hiltunen  10 , Carlos B Duarte  16 , Eero Castrén  17 , Alexandre de Mendonça  9 , Ana M Sebastião  1 , Tiago M Rodrigues  18 , Maria José Diógenes  19
Affiliations

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

João Fonseca-Gomes et al. Mol Ther. .

Erratum in

  • A small TAT-TrkB peptide prevents BDNF receptor cleavage and restores synaptic physiology in Alzheimer's disease.
    Fonseca-Gomes J, Costa-Coelho T, Ferreira-Manso M, Inteiro-Oliveira S, Vaz SH, Alemãn-Serrano N, Atalaia-Barbacena H, Ribeiro-Rodrigues L, Ramalho RM, Pinto R, Miranda HV, Tanqueiro SR, de Almeida-Borlido C, Ramalho MJ, Miranda-Lourenço C, Belo RF, Ferreira CB, Neves V, Rombo DM, Viais R, Umemori J, Martins IC, Jerónimo-Santos A, Caetano A, Manso N, Mäkinen P, Marttinen M, Takalo M, Bremang M, Pike I, Haapasalo A, Loureiro JA, Pereira MC, Santos NC, Outeiro TF, Castanho MARB, Fernandes A, Hiltunen M, Duarte CB, Castrén E, de Mendonça A, Sebastião AM, Rodrigues TM, Diógenes MJ. Fonseca-Gomes J, et al. Mol Ther. 2025 Jan 8;33(1):421. doi: 10.1016/j.ymthe.2024.12.005. Epub 2024 Dec 12. Mol Ther. 2025. PMID: 39672159 Free PMC article. No abstract available.

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, 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.

Keywords: Alzheimer’s disease; BDNF; TAT peptide; TAT-TrkB; TrkB receptor; amyloid β; drug screening; hippocampal plasticity; learning; memory; protein cleavage.

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Conflict of interest statement

Declaration of interests J.F.-G., M.J.D., A.J.-S., C.B.D., and A.M.S. are authors of a patent (application no. PCT/PT2021/050011; priority date: April 1, 2020) concerning the prevention of TrkB-FL cleavage as a therapeutic strategy.

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