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

Fernanda B Lorena1,2, Juliana M Sato1,2, Beatriz Martin Coviello1

  • 1Developmental Disorders Program, Center for Biological Sciences and Health, Mackenzie Presbyterian University, Sao Paulo 01302-907, SP, Brazil.

Metabolites
|July 27, 2022
PubMed

Insights

Age exacerbates cognitive decline in mice with the Thr92Ala-Dio2 polymorphism, linked to reduced thyroid hormone signaling. This study identifies ER stress, Golgi involvement, and hippocampal inflammation as key disease mechanisms.

Area of Science:

  • Neuroscience
  • Genetics
  • Endocrinology

Background:

  • The Thr92Ala-Dio2 polymorphism is linked to cognitive deficits and Alzheimer's disease risk.
  • Reduced thyroid hormone (TH) signaling and endoplasmic reticulum (ER) stress are implicated mechanisms.

Purpose of the Study:

  • To investigate the impact of the Thr92Ala-Dio2 polymorphism on cognition in aging male and female mice.
  • To explore the underlying molecular mechanisms, including TH signaling, ER stress, and other cellular processes.

Main Methods:

  • Utilized the Thr92Ala-Dio2 mouse model across different age groups (young and aged males, adult females).
  • Assessed cognitive function through memory tests.
  • Analyzed gene expression in the prefrontal cortex (PFC) and hippocampus.
  • Investigated the effect of L-T3 treatment on cognitive phenotype.

Main Results:

  • Older male mice and adult female mice with the polymorphism showed more severe cognitive impairment affecting declarative and working memories.
  • No structural changes were observed in the PFC or hippocampus.
  • Gene expression analysis revealed enrichment in TH-dependent processes, ER stress, and Golgi apparatus in the PFC.
  • The hippocampus showed enrichment in genes related to inflammation and apoptosis.
  • L-T3 treatment reversed the cognitive deficits in both sexes, confirming reduced TH signaling as a primary driver.

Conclusions:

  • Age is an additional risk factor for cognitive impairment in the Thr92Ala-Dio2 mouse model.
  • Mechanisms include reduced TH signaling, ER stress, Golgi apparatus involvement, and hippocampal inflammation/apoptosis.
  • Targeting TH signaling may offer therapeutic potential for cognitive dysfunction associated with this polymorphism.
Keywords:
cognitionthyroid hormonetype 2 deiodinase

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