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Assessment of molecular alterations associated with cognitive impairment exhibited by adult mice carrying the Ala92-D2 genetic polymorphism

Grant number: 21/11662-0
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): February 01, 2022
Effective date (End): December 31, 2022
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal researcher:Miriam Oliveira Ribeiro
Grantee:Beatriz Martin Coviello
Home Institution: Centro de Ciências Biológicas e da Saúde (CCBS). Universidade Presbiteriana Mackenzie (UPM). Instituto Presbiteriano Mackenzie. São Paulo , SP, Brazil

Abstract

The Ala92-D2 polymorphism is a genetic mutation in the enzyme that catalyzes the conversion of T4 to T3, the type 2 desiodinase, that is present in a significant portion of the world population (12 to 36%). Ala92-D2 exhibits low catalytic activity, and it is associated with stress of the Rough Endoplasmic Reticulum (RER), memory and exploratory behavior impairment. Previous results from our laboratory shows that memory impairments in Ala92-D2 mice significantly worsens at seven months old. The animal´s performance in the social recognition test is good at 2 months, with the Ala92-D2 animals being able to discriminate between the known and the unknown animal. However, at 7 months old, this ability to discriminate is lost. Considering this data, we hypothesized that the worsening in cognition could be due to the chronification of local hypothyroidism associated with increased oxidative stress and neuroinflammation, the aim of this work is to evaluate molecular changes in Ala92-D2 mice at 2 and 7 months old. If the phenotype abnormalities result from the local hypothyroidism, short-term treatment with T3 (10 days) should be able to reverse them. To test our hypothesis, samples of hippocampus, amygdala, striatum, cerebellum, and prefrontal cortex from 2 and 7 months old Ala92-D2 and Thr92-D2 animals previously frozen at -80°C will be evaluated for transcriptome analysis by RNA sequencing. We will also evaluate the expression of GFAP and NeuN to measure astrogliosis and neuronal degeneration, respectively, by immunohistochemistry. We will assess the enzyme activity, measure oxidative stress by analyzing antioxidant enzymes, damage to total thiols, carbonyls, and reduced and oxidized glutathione. (AU)

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