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Effect of thyroid hormone on the brain of 3xTg-AD mice, model of Alzheimer's Disease, on glucose and cholesterol metabolism

Grant number: 17/07053-3
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): March 01, 2018
Effective date (End): February 28, 2021
Field of knowledge:Health Sciences - Medicine
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Rui Monteiro de Barros Maciel
Grantee:Janaína Sena de Souza
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Associated scholarship(s):18/22763-0 - Ancient DNA, bioengineering and brain "organoids": study of thyroid hormone homeostasis and Alzheimer's Disease markers in NOVA1 gene CRISPR edited stem cells, BE.EP.PD

Abstract

Alzheimer's disease (AD) is a progressive, severe and non-reversible neurodegenerative disease, which begins years before its clinical manifestation. In this disease, dysfunction and deterioration of neurons in the cortical region, inducing loss of memory and progressive decline of cognition, as well as reduced brain volume and this situation could be aggravated by other factors such as changes in thyroid hormone levels (THs), hormones that are involved with brain growth and development in the embryonic and adult stages with maintenance of metabolism and cognitive processes. THs decrease transcription of the amyloid precursor protein (APP) gene and knockout mice to their receptors, increased APP transcription occurs. In AD there is the appearance of metabolic abnormalities in the mitochondria, the use of glucose is 45% decreased, and this parameter is aggravated in the advanced stage of AD, resulting from the oxidative damage caused by the disease. There is a strong genetic link between the apoE isoform µ4 cholesterol carrier and Alzheimer's disease. The lack of ApoE receptor in neurons (LRP1) results in the impairment of dendritic spine formation and neurodegeneration in aging. A brain with neurodegeneration has the inflammatory response activated, and the response is mediated by microglia and astrocytes, causing damage to nervous tissue by releasing cytokines. The objective of this study is to relate the deficiency in glucose and cholesterol metabolism with the role of HT and AD. To do so, we will: (1) study the effect of TH on the gene and protein expression of SREBP-2 and proteins related to cholesterol metabolism in the brain; (2) to study glucose metabolism and the effect of TH on the animal model of AD; (3) to study the inflammatory response in the groups studied. To achieve these objectives we will study gene expression by qPCR, western blot and immunofluorescence protein analysis, and enzyme assay and biochemical studies. With this research we hope to achieve results that can elucidate a few more points of AD and its mechanisms of emergence, and, in this way, make possible new treatments. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
LAUREANO-MELO, ROBERTO; DOS-SANTOS, RAONI CONCEICAO; DA CONCEICAO, RODRIGO RODRIGUES; DE SOUZA, JANAINA SENA; LAU, RAPHAEL DA SILVA; SOUZA SILVA, SAMANTHA DA SILVA; MARINHO, BRUNO GUIMARAES; GIANNOCCO, GISELE; AHMED, R. G.; CORTES, WELLINGTON DA SILVA. Perinatal fluoxetine treatment promotes long-term behavioral changes in adult mice. METABOLIC BRAIN DISEASE, AUG 2020. Web of Science Citations: 0.
DE SOUZA, JANAINA SENA; FERREIRA, DIVINO ROMAO; HERAI, ROBERTO; CARROMEU, CASSIANO; TORRES, LAILA BRITO; SILVA ARAUJO, BRUNO HENRIQUE; CUGOLA, FERNANDA; MACIEL, RUI M. B.; MUOTRI, ALYSSON RENATO; GIANNOCCO, GISELE. Altered Gene Expression of Thyroid Hormone Transporters and Deiodinases in iPS MeCP2-Knockout Cells-Derived Neurons. Molecular Neurobiology, v. 56, n. 12, p. 8277-8295, DEC 2019. Web of Science Citations: 0.
DE SOUZA, JANAINA SENA; LAUREANO-MELO, ROBERTO; HERAI, ROBERTO HIROCHI; DA CONCEICAO, RODRIGO RODRIGUES; OLIVEIRA, KELEN CARNEIRO; COTRIM GUERREIRO DA SILVA, ISMAEL DALE; DIAS-DA-SILVA, MAGNUS REGIOS; ROMANO, RENATA MARINO; ROMANO, MARCO AURELIO; DE BARROS MACIEL, RUI MONTEIRO; CHIAMOLERA, MARIA IZABEL; GIANNOCCO, GISELE. Maternal glyphosate-based herbicide exposure alters antioxidant-related genes in the brain and serum metabolites of male rat offspring. NeuroToxicology, v. 74, p. 121-131, SEP 2019. Web of Science Citations: 0.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.