An Alzheimer Disease-like model in "Nothobranchius furzeri": Optimization of Aβ42 injection and evaluation of age-related learning deficits

Details

Supervisors

Page, Melissa ; Poyraz, Yusuf Kaan

Faculty

Faculté des sciences

Degree label

Master [120] en biochimie et biologie moléculaire et cellulaire, à finalité approfondie

Abstract

enAlzheimer’s disease (AD) is a progressive neurodegenerative disease being the most common form of dementia. This disorder is characterized by early intracellular amyloid beta (Aβ) accumulation, followed by late-stage hallmarks such as extracellular Aβ plaques deposition, hyperphosphorylated tau neurofibrillary tangles, neuroinflammation, and neuronal cell death. The African turquoise killifish ("Nothobranchius furzeri") has recently emerged as a promising vertebrate model for aging research and exhibits age-associated accumulation of intramitochondrial Aβ, making it a potential model to study the early stages of AD. The first objective of this study was to investigate whether age-related intramitochondrial Aβ accumulation in "N. furzeri" correlates with cognitive decline using the active avoidance assay. This test revealed an age-dependent decrease in avoidance rate in aged fish, indicating cognitive impairment. However, this model does not naturally present key late-stage AD hallmarks such as extracellular Aβ plaques. Therefore, the second objective was to optimize cerebroventricular microinjection (CVMI) of human Aβ42 (hAβ42) in "N. furzeri" to induce such late-stage AD-like characteristics. Monomeric hAβ42 was injected at different concentrations, and its effect on amyloidogenic gene expression, Aβ levels, microglial abundance and activation, synaptic levels as well as apoptosis were evaluated using RT-qPCR and immunofluorescence staining. While, hAβ42 injection did not induce upregulation of amyloidogenic gene expression, it resulted in increased total Aβ levels, synaptic loss and microglial quantity and markers of activity in a dose-dependent manner. However, no significant increase in apoptotic gene expression was observed. Overall, these findings suggest that "N. furzeri" naturally develops early AD-like features with advanced age, and that acute hAβ42 exposure can partially trigger late-stage hallmarks. In the future, additional injections and experiments will be required to determine the optimal hAβ42 concentration necessary to induce late-stage AD.