Age Worsens the Cognitive Phenotype in Mice Carrying the Thr92Ala-DIO2 Polymorphism

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Lorena, Fernanda B. ; Sato, Juliana M. ; Coviello, Beatriz Martin ; Arnold, Alexandre J. T. ; Batistuzzo, Alice ; Yamanouchi, Lais M. ; Dias Junior, Eduardo ; do Nascimento, Bruna P. P. ; Fonseca, Tatiana de L. ; Bianco, Antonio C. ; Ribeiro, Miriam O.

• Tipo de documento: Artigo Científico
• Fonte: METABOLITES; v. 12, n. 7, p. 14-pg., 2022-07-01.

Resumo

The Thr92Ala-Dio2 polymorphism has been associated with reduced cognition in 2-month-old male mice and increased risk for cognitive impairment and Alzheimer's disease in African Americans. This has been attributed to reduced thyroid hormone (TH) signaling and endoplasmic reticulum (ER) stress in the brain. Here we studied the Thr92Ala-Dio2 mouse model and saw that older male mice (7-8-month-old) exhibited a more severe cognition impairment, which extended to different aspects of declarative and working memories. A similar phenotype was observed in 4-5-month-old female mice. There were no structural alterations in the prefrontal cortex (PFC) and hippocampus of the Thr92Ala-Dio2 mouse. Nonetheless, in both male and female PFC, there was an enrichment in genes associated with TH-dependent processes, ER stress, and Golgi apparatus, while in the hippocampus there was additional enrichment in genes associated with inflammation and apoptosis. Reduced TH signaling remains a key mechanism of disease given that short-term treatment with L-T3 rescued the cognitive phenotype observed in males and females. We conclude that in mice, age is an additional risk factor for cognitive impairment associated with the Thr92Ala-Dio2 polymorphism. In addition to reduced TH signaling, ER-stress, and involvement of the Golgi apparatus, hippocampal inflammation and apoptosis were identified as potentially important mechanisms of a disease. (AU)

• Processo FAPESP: 17/04491-0 - Efeito do análogo do hormônio tireoideano seletivo para o TRbeta, GC-1, no cérebro de camundongos 3xTg-AD
• Beneficiário: Bruna Pascarelli Pedrico Do Nascimento
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 17/18277-0 - Correlação entre o polimorfismo Thr92Ala da enzima iodotironina desiodase do tipo 2 (D2) e comportamento.
• Beneficiário: Miriam Oliveira Ribeiro
• Modalidade de apoio: Auxílio à Pesquisa - Regular