Evaluation of molecular changes associated with ageing in a Down syndrome animal model

Author(s)

Larissa Estessi de Souza

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD)
• Defense date: 2024-08-06

Examining board members

Daniele de Paula Faria; Luiz Roberto Giorgetti de Britto; Marcelo Tatit Sapienza; Daniella Balduino Victorino

• Advisor: Daniele de Paula Faria

Abstract

Introduction: Down syndrome (DS) is a genetic disorder of chromosome 21 that causes intellectual disability. Individuals with DS have a high risk of developing Alzheimer\'s disease (AD), which is a neurodegenerative disease characterized by the formation of beta-amyloid plaques and neurofibrillary tangles. The life expectancy of people with DS has increased in recent decades, making ageing an important new area of study in DS. Positron emission tomography (PET) imaging is a sensitive method that detects physiological changes, allowing non-invasive in vivo study of molecular processes, being an important tool for understanding the aging process. Objective: To evaluate the molecular changes (glial activation, brain metabolism, and white matter changes) associated with aging and the role of treatment with microdosing of lithium carbonate in a mouse model of Down syndrome (Ts65Dn mice) using PET imaging. Methods: Ts65Dn animals were evaluated at 2, 5, 14, 20, and 24 months of age using PET imaging to assess myelin content (with [11C]PIB), neuroinflammation (with [11C]PK11195), and glucose metabolism ([18F]FDG). Behavioral tests (open field and novel object recognition) and immunohistochemical analysis were also performed in this study. One group was treated with lithium carbonate at a microdosing of 0.25 mg/kg dissolved in water and examined at the same age as the untreated animals. Results: The behavioral tests showed hyperactivity in the trisomic animals in the first months of life, which was reduced in the lithium-treated animals. In short-term memory, trisomic animals performed worse in the first months of life than euploid animals, while in long-term memory, performance was significantly lower at 24 months of age. Lithium treatment did not alter the memory results. In PET images, the animals (trisomic and euploid) showed an increase in [11C]PIB uptake from two to five months of age, indicating a probable increase in myelin of these animals, while the lithium-treated animals showed lower uptake at 5 and 14 months of age. An increase in [11C]PK11195 uptake was detected at 5 and 14 months in trisomic and euploid animals, but uptake decreased in lithium-treated trisomic animals. In [18F]FDG PET, an increase in uptake was also observed at 14 months, corroborating the data observed with the [11C]PK11195 images, and a decrease was detected at 24 months. Immunohistochemistry demonstrated that the increase in [11C]PK11195 and [18F]FDG uptakes were associated with an inflammatory process. Conclusion: PET imaging with different tracers was able to monitor molecular differences during aging of the Ts65Dn strain, such as myelination at a young age, followed by a process of neuroinflammation and decrease in brain metabolism. The results of lithium treatment were promising for use in Down syndrome (AU)

• FAPESP's process: 19/15654-2 - Evaluation of molecular changes associated with aging in the Down Syndrome animal model
• Grantee: Larissa Estessi de Souza
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)