Age Worsens the Cognitive Phenotype in Mice Carrying the Thr92Ala-DIO2 Polymorphism
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...
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MDPI AG
2022-07-01
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| author | Fernanda B. Lorena Juliana M. Sato Beatriz Martin Coviello Alexandre J. T. Arnold Alice Batistuzzo Laís M. Yamanouchi Eduardo Dias Junior Bruna P. P. do Nascimento Tatiana de L. Fonseca Antonio C. Bianco Miriam O. Ribeiro |
| author_facet | Fernanda B. Lorena Juliana M. Sato Beatriz Martin Coviello Alexandre J. T. Arnold Alice Batistuzzo Laís M. Yamanouchi Eduardo Dias Junior Bruna P. P. do Nascimento Tatiana de L. Fonseca Antonio C. Bianco Miriam O. Ribeiro |
| author_sort | Fernanda B. Lorena |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T06:13:07Z |
| format | Article |
| id | doaj.art-dc73b6f076b54ed592ad014f4608d1b0 |
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| issn | 2218-1989 |
| language | English |
| last_indexed | 2024-03-09T06:13:07Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Metabolites |
| spelling | doaj.art-dc73b6f076b54ed592ad014f4608d1b02023-12-03T11:57:05ZengMDPI AGMetabolites2218-19892022-07-0112762910.3390/metabo12070629Age Worsens the Cognitive Phenotype in Mice Carrying the Thr92Ala-DIO2 PolymorphismFernanda B. Lorena0Juliana M. Sato1Beatriz Martin Coviello2Alexandre J. T. Arnold3Alice Batistuzzo4Laís M. Yamanouchi5Eduardo Dias Junior6Bruna P. P. do Nascimento7Tatiana de L. Fonseca8Antonio C. Bianco9Miriam O. Ribeiro10Developmental Disorders Program, Center for Biological Sciences and Health, Mackenzie Presbyterian University, Sao Paulo 01302-907, SP, BrazilDevelopmental Disorders Program, Center for Biological Sciences and Health, Mackenzie Presbyterian University, Sao Paulo 01302-907, SP, BrazilDevelopmental Disorders Program, Center for Biological Sciences and Health, Mackenzie Presbyterian University, Sao Paulo 01302-907, SP, BrazilDevelopmental Disorders Program, Center for Biological Sciences and Health, Mackenzie Presbyterian University, Sao Paulo 01302-907, SP, BrazilDevelopmental Disorders Program, Center for Biological Sciences and Health, Mackenzie Presbyterian University, Sao Paulo 01302-907, SP, BrazilDevelopmental Disorders Program, Center for Biological Sciences and Health, Mackenzie Presbyterian University, Sao Paulo 01302-907, SP, BrazilDevelopmental Disorders Program, Center for Biological Sciences and Health, Mackenzie Presbyterian University, Sao Paulo 01302-907, SP, BrazilDevelopmental Disorders Program, Center for Biological Sciences and Health, Mackenzie Presbyterian University, Sao Paulo 01302-907, SP, BrazilSection of Adult and Pediatric Endocrinology, Diabetes and Metabolism, University of Chicago, Chicago, IL 60637, USASection of Adult and Pediatric Endocrinology, Diabetes and Metabolism, University of Chicago, Chicago, IL 60637, USADevelopmental Disorders Program, Center for Biological Sciences and Health, Mackenzie Presbyterian University, Sao Paulo 01302-907, SP, BrazilThe 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.https://www.mdpi.com/2218-1989/12/7/629thyroid hormonecognitiontype 2 deiodinase |
| spellingShingle | Fernanda B. Lorena Juliana M. Sato Beatriz Martin Coviello Alexandre J. T. Arnold Alice Batistuzzo Laís M. Yamanouchi Eduardo Dias Junior Bruna P. P. do Nascimento Tatiana de L. Fonseca Antonio C. Bianco Miriam O. Ribeiro Age Worsens the Cognitive Phenotype in Mice Carrying the Thr92Ala-DIO2 Polymorphism Metabolites thyroid hormone cognition type 2 deiodinase |
| title | Age Worsens the Cognitive Phenotype in Mice Carrying the Thr92Ala-DIO2 Polymorphism |
| title_full | Age Worsens the Cognitive Phenotype in Mice Carrying the Thr92Ala-DIO2 Polymorphism |
| title_fullStr | Age Worsens the Cognitive Phenotype in Mice Carrying the Thr92Ala-DIO2 Polymorphism |
| title_full_unstemmed | Age Worsens the Cognitive Phenotype in Mice Carrying the Thr92Ala-DIO2 Polymorphism |
| title_short | Age Worsens the Cognitive Phenotype in Mice Carrying the Thr92Ala-DIO2 Polymorphism |
| title_sort | age worsens the cognitive phenotype in mice carrying the thr92ala dio2 polymorphism |
| topic | thyroid hormone cognition type 2 deiodinase |
| url | https://www.mdpi.com/2218-1989/12/7/629 |
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