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Adenosinergic system and BDNF signaling changes as a cross-sectional feature of RTT: characterization of Mecp2 heterozygous mouse females

Publication . Miranda-Lourenço, Catarina; Rosa, Jéssica; Rei, Nádia; Belo, Rita F.; Lopes, Ana Luísa; Silva, Diogo; Vieira, Cátia; Magalhães-Cardoso, Teresa; Viais, Ricardo; Correia-de-Sá, Paulo; Sebastião, Ana M; Diógenes, Maria José

Rett Syndrome is an X-linked neurodevelopmental disorder (RTT; OMIM#312750) associated to MECP2 mutations. MeCP2 dysfunction is seen as one cause for the deficiencies found in brain-derived neurotrophic factor (BDNF) signaling, since BDNF is one of the genes under MeCP2 jurisdiction. BDNF signaling is also dependent on the proper function of the adenosinergic system. Indeed, both BDNF signaling and the adenosinergic system are altered in Mecp2-null mice (Mecp2-/y), a representative model of severe manifestation of RTT. Considering that symptoms severity largely differs among RTT patients, we set out to investigate the BDNF and ADO signaling modifications in Mecp2 heterozygous female mice (Mecp2+/-) presenting a less severe phenotype. Symptomatic Mecp2+/- mice have lower BDNF levels in the cortex and hippocampus. This is accompanied by a loss of BDNF-induced facilitation of hippocampal long-term potentiation (LTP), which could be restored upon selective activation of adenosine A2A receptors (A2AR). While no differences were observed in the amount of adenosine in the cortex and hippocampus of Mecp2+/- mice compared with healthy littermates, the density of the A1R and A2AR subtype receptors was, respectively, upregulated and downregulated in the hippocampus. Data suggest that significant changes in BDNF and adenosine signaling pathways are present in an RTT model with a milder disease phenotype: Mecp2+/- female animals. These features strengthen the theory that boosting adenosinergic activity may be a valid therapeutic strategy for RTT patients, regardless of their genetic penetrance.

2023Journal article

Open access

Intestinal tissue-resident T cell activation depends on metabolite availability

Publication . Konjar, Spela; Ferreira, Cristina; Carvalho, Filipa; Figueiredo-Campos, Patricia; Fanczal, Júlia; Ribeiro, Sofia; Morais, Vanessa A.; Veldhoen, Marc

The metabolic capacity of many cells is tightly regulated and can adapt to changes in metabolic resources according to environmental changes. Tissue-resident memory (TRM) CD8+ T cells are one of the most abundant T cell populations and offer rapid protection against invading pathogens, especially at the epithelia. TRM cells metabolically adapt to their tissue niche, such as the intestinal epithelial barrier. In the small intestine, the types of TRM cells are intraepithelial lymphocytes (IELs), which contain high levels of cytotoxic molecules and express activation markers, suggesting a heightened state of activation. We hypothesize that the tissue environment may determine IEL activity. We show that IEL activation, in line with its semiactive status, is metabolically faster than circulating CD8+ T cells. IEL glycolysis and oxidative phosphorylation (OXPHOS) are interdependently regulated and are dependent on rapid access to metabolites from the environment. IELs are restrained by local availability of metabolites, but, especially, glucose levels determine their activity. Importantly, this enables functional control of intestinal TRM cells by metabolic means within the fragile environment of the intestinal epithelial barrier.

2022Journal article

Open access

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

Publication . 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 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

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.

2024Journal article

Open access