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Assessing plasma BDNF receptor cleavage in Alzheimer’s disease
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Resumo(s)
A doença de Alzheimer (DA) é uma doença neurodegenerativa comum. É classificada em três estadios: uma fase assintomática, uma fase de défice cognitivo ligeiro (DCL), e demência. A sua fisiopatologia envolve a produção de péptidos de beta-amilóide (Aβ). Na DA, a sinalização mediada pelo factor neurotrófico derivado do cérebro (BDNF) através do receptor TrkB-FL está perturbada. Um dos mecanismos causais envolve a clivagem do receptor TrkB-FL por calpaínas, promovido pela acumulação de Aβ. O fragmento intracelular resultante (TrkB-ICD) encontra-se elevado em amostras de cécebro pós-mortem de doentes com DA, enquanto níveis de TrkB-FL se encontram diminuidos. Os níveis de TrkB-ICD também estão aumentados no líquido cefalorraquidiano (LCR) de doentes com DCL devido a DA. Recentemente, um novo composto capaz de prevenir a clivagem do TrkB-FL foi desenvolvido, denominado TAT-TrkB. Para monitorização terapêutica segura da administração de TAT-TrkB, seria útil desenvolver um biomarcador plasmático. O objectivo principal deste trabalho é então avaliar as diferenças nos níveis plasmáticos de TrkB-FL e TrkB-ICD em doentes com DCL devido a DA. A metodologia passa pela optimização do protocolo de detecção em murganhos wild-type e aplicação subsequente em amostras humanas de doentes com DCL devido a DA e controlos. Os resultados mostram uma diminuição nos níveis de TrkB-FL e TrkB-ICD no plasma dos doentes com DCL devido a DA, quando comparados a um grupo com DCL sem critérios de DA. O rácio TrkB-FL/TrkB-ICD não mostrou diferenças entre os grupos. Estes resultados sugerem que o TrkB-ICD não pode ainda ser proposto como biomarcador para DCL devido a DA. Futuramente, será necessária uma pesquisa mais aprofundada para (1) verificar os dados controlando o erro, e (2) clarificar a presença de um ou múltiplos factores externos que possam influenciar os níveis periféricos destas proteínas.
Alzheimer’s Disease (AD) is a common neurodegenerative disorder. It is classified into three stages: an asymptomatic stage, mild cognitive impairment (MCI) stage, and dementia. Its pathology involves the production of amyloid beta peptides (Aβ). In AD, signalling mediated by the brain-derived neurotrophic factor (BDNF) through the TrkB-FL receptor is impaired. One of the causal mechanisms involves cleavage of the TrkB-FL receptor by calpains, promoted by Aβ accumulation. The resulting intracellular fragment (TrkB-ICD) is increased in post-mortem brain samples of AD patients, while levels of TrkB-FL are decreased. TrkB-ICD levels are also increased in cerebrospinal fluid (CSF) of patients with MCI due to AD. Recently, a new compound has been developed that is able to prevent TrkB-FL cleavage, designated TAT-TrkB. For safe and cost-effective therapeutic monitorization of TAT-TrkB administration in patients, it would be useful to develop reliable bloodbased biomarker. Therefore, the primary aim of this project is to assess differences in plasma levels of TrkB-FL and TrkB-ICD in patients with MCI due to AD. The methodology includes optimization of the detection protocol in wild-type mice and subsequent application in human samples from patients with MCI due to AD and controls. Results show levels of TrkB-FL and TrkB-ICD to be decreased in the plasma of MCI due to AD patients, when compared to an MCI group without AD criteria, while the TrkBFL/ TrkB-ICD ratio showed no differences between the groups. These results suggest that TrkB-ICD cannot yet be proposed as a potential biomarker for MCI due to AD. Futurely, more thorough research is needed to (1) verify the data and control for error, and to (2) clarify the presence of one or multiple unknown factors that may influence the peripheral levels of these proteins.
Alzheimer’s Disease (AD) is a common neurodegenerative disorder. It is classified into three stages: an asymptomatic stage, mild cognitive impairment (MCI) stage, and dementia. Its pathology involves the production of amyloid beta peptides (Aβ). In AD, signalling mediated by the brain-derived neurotrophic factor (BDNF) through the TrkB-FL receptor is impaired. One of the causal mechanisms involves cleavage of the TrkB-FL receptor by calpains, promoted by Aβ accumulation. The resulting intracellular fragment (TrkB-ICD) is increased in post-mortem brain samples of AD patients, while levels of TrkB-FL are decreased. TrkB-ICD levels are also increased in cerebrospinal fluid (CSF) of patients with MCI due to AD. Recently, a new compound has been developed that is able to prevent TrkB-FL cleavage, designated TAT-TrkB. For safe and cost-effective therapeutic monitorization of TAT-TrkB administration in patients, it would be useful to develop reliable bloodbased biomarker. Therefore, the primary aim of this project is to assess differences in plasma levels of TrkB-FL and TrkB-ICD in patients with MCI due to AD. The methodology includes optimization of the detection protocol in wild-type mice and subsequent application in human samples from patients with MCI due to AD and controls. Results show levels of TrkB-FL and TrkB-ICD to be decreased in the plasma of MCI due to AD patients, when compared to an MCI group without AD criteria, while the TrkBFL/ TrkB-ICD ratio showed no differences between the groups. These results suggest that TrkB-ICD cannot yet be proposed as a potential biomarker for MCI due to AD. Futurely, more thorough research is needed to (1) verify the data and control for error, and to (2) clarify the presence of one or multiple unknown factors that may influence the peripheral levels of these proteins.
Descrição
Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2022
Palavras-chave
Doença de Alzheimer Fator neurotrófico derivado do cérebro (BDNF) Receptor TrkB-FL Fragmento intracelular resultante (TrkB-ICD) Biomarcadores Neurociências