Avaliação dos efeitos da privação de sono aguda no metabolismo de peptídeos beta-amiloide
Arquivos
Data
2022-03-07
Autores
Luz, Márcio Henrique Mello da [UNIFESP]
Orientadores
Lee, Kil Sun [UNIFESP]
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
A doença de Alzheimer (DA) é uma doença neurodegenerativa, marcada por um declínio cognitivo progressivo e pelo acometimento de indivíduos em idade avançada. Esta doença é caracterizada molecularmente pelo acúmulo de emaranhados neurofibrilares compostos de proteína tau e placas senis formadas por agregados de peptídeo β-amiloide (Aβ). Ainda, nos pacientes com a DA há uma maior prevalência do alelo ε4, que codifica a variante E4 da apolipoproteína E (APOE). Outra característica observada nestes pacientes é que eles costumam apresentar alteração no perfil de sono. Por outro lado, a privação de sono (PS) também pode ser considerada um fator de risco para o desenvolvimento da DA, uma vez que a falta de sono causa o acúmulo de Aβ no cérebro. Este acúmulo pode ter relação com a atividade exercida por APOE na depuração de Aβ, uma vez que os hormônios alterados pela PS são capazes de regular a expressão da APOE. Dessa forma, o objetivo principal deste trabalho foi estudar os efeitos gerados pela privação de sono no metabolismo de Aβ. Os resultados desta tese estão apresentados em dois capítulos correspondentes a estudos paralelos realizados durante o mesmo período. No primeiro capítulo está descrito o efeito causado pelo uso de Ketamina e Xilazina antes da eutanásia de ratos do tipo Wistar. O uso destes anestésicos causou alteração no nível do hormônio corticosterona, além de redução na ativação de MAPK e de SRC quinases. Estes resultados demonstram a importância de se avaliar o uso de anestésico como um critério a priori do estudo. Já no segundo capítulo, foi descrito o papel de APOE e de seus receptores no metabolismo de Aβ quando em situação de PS. Para isso, ratos foram privados de sono de forma aguda por um período de 96 horas consecutivas. Após a PS, foi observado acúmulo de Aβ e diminuição de APOE e seu receptor LRP1 no hipocampo destes animais. Além dessas alterações, a PS foi responsável por alterar os níveis séricos de hormônios tireoidianos, que por vez podem modular a expressão de APOE. Em modelo in vitro, utilizando células de linhagem endotelial cerebral e células C6 de glioma tratadas com IL-6 e T4, observamos que a variação na concentração de T4 pode ser responsável pela disponibilidade dos receptores de APOE, e, desta forma, alterar a captação de peptídeos e outros ligantes via estes receptores. Palavras-Chave: Privação de Sono; Peptídeos
Alzheimer's disease (AD) is a neurodegenerative disease, marked by a progressive cognitive decline and for affecting elderly people. This disease is molecularly characterized by the accumulations of neurofibrillary tangles composed of tau protein and senile plaques formed by aggregates of β-amyloid peptide (Aβ). Furthermore, in AD patients there is a higher prevalence of the ε4 allele, which encodes the E4 variant of apolipoprotein E (APOE). Another characteristic observed in these patients, is that they usually present an alteration in their sleep profile. On the other hand, sleep deprivation (SD) can also be considered as a risk factor for the development of AD, since the lack of sleep causes the accumulation of Aβ in the brain. This accumulation may be related to the activity exerted by APOE in the Aβ clearance, since the hormones altered by SD are able to regulate the APOE expression. Thus, the main objective of this work was to study the effects generated by sleep deprivation on the metabolism of β-amyloid peptides (Aβ). The results of this thesis are presented in two chapters corresponding to parallel studies carried out during the same period. The first chapter describes the effect caused by the of Ketamine and Xylazine prior to euthanasia of Wistar rats. The use of these anesthetics altered corticosterone levels and also reduced the activation of MAPK and SRC kinases. These results demonstrate the importance of evaluating the use of anesthetics as an a priori criteria of the study. In the second chapter, the role of APOE and its receptors in Aβ metabolism in case of SD was described. For this, rats were acutely sleep deprived for 96 consecutive hours. After SD, Aβ accumulation and decrease of APOE and its receptor LRP1 were observed in the hippocampus of these animals. In addition to these changes, SD was responsible for altering the serum levels of thyroid hormones, which in turn can modulate the expression of APOE. In an in vitro model, using brain endothelial and C6 glioma cells that were treated with IL-6 and T4, we observed that the variation in T4 concentration may be responsible for the availability of APOE receptors, thus, being capable to alter the uptake of peptides and other ligands via these receptors.
Alzheimer's disease (AD) is a neurodegenerative disease, marked by a progressive cognitive decline and for affecting elderly people. This disease is molecularly characterized by the accumulations of neurofibrillary tangles composed of tau protein and senile plaques formed by aggregates of β-amyloid peptide (Aβ). Furthermore, in AD patients there is a higher prevalence of the ε4 allele, which encodes the E4 variant of apolipoprotein E (APOE). Another characteristic observed in these patients, is that they usually present an alteration in their sleep profile. On the other hand, sleep deprivation (SD) can also be considered as a risk factor for the development of AD, since the lack of sleep causes the accumulation of Aβ in the brain. This accumulation may be related to the activity exerted by APOE in the Aβ clearance, since the hormones altered by SD are able to regulate the APOE expression. Thus, the main objective of this work was to study the effects generated by sleep deprivation on the metabolism of β-amyloid peptides (Aβ). The results of this thesis are presented in two chapters corresponding to parallel studies carried out during the same period. The first chapter describes the effect caused by the of Ketamine and Xylazine prior to euthanasia of Wistar rats. The use of these anesthetics altered corticosterone levels and also reduced the activation of MAPK and SRC kinases. These results demonstrate the importance of evaluating the use of anesthetics as an a priori criteria of the study. In the second chapter, the role of APOE and its receptors in Aβ metabolism in case of SD was described. For this, rats were acutely sleep deprived for 96 consecutive hours. After SD, Aβ accumulation and decrease of APOE and its receptor LRP1 were observed in the hippocampus of these animals. In addition to these changes, SD was responsible for altering the serum levels of thyroid hormones, which in turn can modulate the expression of APOE. In an in vitro model, using brain endothelial and C6 glioma cells that were treated with IL-6 and T4, we observed that the variation in T4 concentration may be responsible for the availability of APOE receptors, thus, being capable to alter the uptake of peptides and other ligands via these receptors.
Descrição
Citação
LUZ, Márcio Henrique Mello da. Avaliação dos efeitos da privação de sono aguda no metabolismo de peptídeos beta-amiloide. São Paulo, 2022. 107 p. Tese (Doutorado em Ciências Biológicas: Biologia Molecular) – Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, 2022.