Year: 2024
Type: dissertation
Abstract: Alzheimer's disease(AD) is a neurodegenerative condition that hinders thinking, memory and behavior. Two of the main brain abnormalities linked to AD are the buildup of beta-amyloid (Αβ) into aggregates outside of neurons and the accumulation of the protein tau inside the neurons. In addition, myelin degeneration has also been widely documented in AD patients and animal models. Demyelination is an early event that emerges before tau and Αβ pathologies, and even before atrophy of white and gray matter, and has also been observed in the fornix. Fornix is a thin C-shaped bundle of the white matter consisting of myelinated fibers, implicated in episodic memory. Moreover, in the initial stages of AD, oligodendrocyte (OLs) abnormalities were found to undergo significant alterations linked to cognitive decline. Another trait observed during AD, is the excessive release of glutamate into the extracellular space by pre-synaptic nerve terminals that causes excitotoxicity by overstimulating NMDA receptors and impaired glutamate uptake by EAAT. Furthermore, functional NMDA receptors are expressed on the myelin sheath, that could partially provoke paranodal myelin damage in response to elevated glutamate levels. This work aims to address the fact that demyelination and alterations in oligodendrocyte lineage cells occur specifically at the dorsal fornix (df), in young transgenic mice, before the development of cognitive impairment. Another goal is to demonstrate that the rise in glutamate is due to amyloid increase in cultured neurons. Glutamate could leak out of axons and bind to NMDA receptors and EAATs, causing myelin damage. The obtained results demonstrated a significant decrease in the levels of myelin components in the df of APP/PS1 mice compared to controls, while the levels of neuraxon marker were unchanged. Additionally, it was observed an increase in the levels of oligodendrocyte progenitor cells, and at the same time, a significant decrease of mature myelinating OLs. Simultaneously, these alterations were not detected in their hippocampi. In neurosphere cultures, treatment with Αβ resulted in a significant decrease of myelin levels. Co-treatment with DLTBOA, a competitive blocker of EAAT, reversed efficiently this decline. There were no appreciable changes in myelin levels in the combined treatment of Αβ with QN46, a non-competitive NMDA antagonist, when compared to Αβ-treated group. Additionally, the population of neurons was unaffected by Αβ treatment, and no notable differences were seen under any circumstances. In conclusion, APP/PS1 mice exhibit demyelination of the df accompanied by changes in oligodenrocyte lineage cells. In neurosphere cultures, Αβ-treated cells also undergo demyelination, which was reverted after DL-TBOA treatment. This implies that Αβ-induced glutamate excitotoxicity may be a potential mechanism of myelin degeneration.
Author: Ftara, Artemis
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7019867261