Efeito do polimorfismo THR92ALA-D2 no comportamento de camundongos machos adultos
Data
2022-04-28
Autores
Sato, Juliana Midori [UNIFESP]
Orientadores
Ribeiro, Miriam Oliveira
Tipo
Dissertação de mestrado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
A presença do polimorfismo Ala92-D2 está associada a prejuízos moderados na
memória em animais jovens. Considerando que o envelhecimento per se leva à prejuízos
na cognição, nós levantamos a hipótese de que a presença do polimorfismo pode ser um
agravante para essa condição em animais envelhecidos. A alta prevalência do polimorfismo
Ala92-D2 na população mundial (12 a 36%) torna relevante a compreensão do seu impacto
na cognição. Para testar a nossa hipótese avaliamos a memória declarativa, viso espacial
e de trabalho em camundongos Ala92-D2 aos dois e sete meses de idade. O
envelhecimento associado ao polimorfismo Ala92-D2 reduziu a atividade locomotora, levou
a prejuízos na memória declarativa e na memória de trabalho. O tratamento com T3 a curto
prazo reverteu todas as alterações observadas, sugerindo que o hipotiroidismo resultante
da menor atividade catalítica da Ala92-D2 pode estar envolvido na gênese desse fenótipo.
A análise do transcriptoma por RNA-sequencing no hipocampo e córtex dos animais Thr92-
D2 e Ala92-D2 mostrou alterações na expressão de diversos genes associados com
cognição, tais como Gabra2, Nrg4, Rgs9, Drd1 e 2, Ppp1r1b, Gpr52, Gpr6 e 88.
Supreendentemente, nenhum deles é regulado pelo Hormônio Tiroidiano. Em conclusão, a
presença do polimorfismo Ala92-D2 causa prejuízos significativos à cognição de
camundongos envelhecidos.
The presence of the Ala92-D2 polymorphism is associated with moderate impairments in memory in young animals. Considering that aging per se leads to impairments in cognition, we hypothesized that the presence of polymorphism may be an aggravating factor for this condition in aged animals. The high prevalence of the Ala92-D2 polymorphism in the world population (12 to 36%) makes it relevant to understand its impact on cognition. To test our hypothesis we evaluated declarative, spatial vision and working memory in Ala92-D2 mice at two and seven months of age. Aging associated with the Ala92-D2 polymorphism reduced locomotor activity, leading to impairments in declarative memory and working memory. Short-term LT3 treatment reversed all observed changes, suggesting that hypothyroidism resulting from the lower catalytic activity of Ala92-D2 may be involved in the genesis of this phenotype. The transcriptome analysis by RNA-sequencing in the hippocampus and cortex of Thr92-D2 and Ala92-D2 animals showed changes in the expression of several genes associated with cognition, such as Gabra2, Nrg4, Rgs9, Drd1 and 2, Ppp1r1b, Gpr52, Gpr6 and 88. Surprisingly, none of them are regulated by Thyroid Hormone. In conclusion, the presence of the Ala92-D2 polymorphism causes significant damage to the cognition of aged mice.
The presence of the Ala92-D2 polymorphism is associated with moderate impairments in memory in young animals. Considering that aging per se leads to impairments in cognition, we hypothesized that the presence of polymorphism may be an aggravating factor for this condition in aged animals. The high prevalence of the Ala92-D2 polymorphism in the world population (12 to 36%) makes it relevant to understand its impact on cognition. To test our hypothesis we evaluated declarative, spatial vision and working memory in Ala92-D2 mice at two and seven months of age. Aging associated with the Ala92-D2 polymorphism reduced locomotor activity, leading to impairments in declarative memory and working memory. Short-term LT3 treatment reversed all observed changes, suggesting that hypothyroidism resulting from the lower catalytic activity of Ala92-D2 may be involved in the genesis of this phenotype. The transcriptome analysis by RNA-sequencing in the hippocampus and cortex of Thr92-D2 and Ala92-D2 animals showed changes in the expression of several genes associated with cognition, such as Gabra2, Nrg4, Rgs9, Drd1 and 2, Ppp1r1b, Gpr52, Gpr6 and 88. Surprisingly, none of them are regulated by Thyroid Hormone. In conclusion, the presence of the Ala92-D2 polymorphism causes significant damage to the cognition of aged mice.