Lorena Fernanda B, Sato Juliana M, Coviello Beatriz Martin, Arnold Alexandre J T, Batistuzzo Alice, Yamanouchi Laís M, Dias Junior Eduardo, do Nascimento Bruna P P, Fonseca Tatiana de L, Bianco Antonio C, Ribeiro Miriam O
Developmental Disorders Program, Center for Biological Sciences and Health, Mackenzie Presbyterian University, Sao Paulo 01302-907, SP, Brazil.
Postgraduate Program in Translational Medicine, Department of Medicine, Paulista School of Medicine, Federal University of Sao Paulo, Sao Paulo 04021-001, SP, Brazil.
Metabolites. 2022 Jul 8;12(7):629. doi: 10.3390/metabo12070629.
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.
Thr92Ala-Dio2基因多态性与2月龄雄性小鼠认知能力下降以及非裔美国人认知障碍和阿尔茨海默病风险增加有关。这归因于大脑中甲状腺激素（TH）信号传导减少和内质网（ER）应激。在此，我们研究了Thr92Ala-Dio2小鼠模型，发现老年雄性小鼠（7-8月龄）表现出更严重的认知障碍，这种障碍扩展到陈述性记忆和工作记忆的不同方面。在4-5月龄雌性小鼠中也观察到类似的表型。Thr92Ala-Dio2小鼠的前额叶皮层（PFC）和海马体没有结构改变。尽管如此，在雄性和雌性PFC中，与TH依赖过程、ER应激和高尔基体相关的基因均有富集，而在海马体中，与炎症和凋亡相关的基因有额外富集。鉴于用L-T3进行短期治疗可挽救雄性和雌性小鼠中观察到的认知表型，TH信号传导减少仍然是疾病的关键机制。我们得出结论，在小鼠中，年龄是与Thr92Ala-Dio2基因多态性相关的认知障碍的一个额外风险因素。除了TH信号传导减少、ER应激和高尔基体的参与外，海马体炎症和凋亡被确定为该疾病潜在的重要机制。
