The role of ANG and tRNA-derived fragments in aging, neurodegeneration and the pathophysiology of Alzheimer’s Disease.

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disease, characterized by gradual cognitive decline and later dementia. About 15% of the over-65s and over 50% of the over-80s are affected by AD worldwide. Despite intensive basic research, the pathogenesis of AD is only partially understood. This project focused on the expression of the ribonuclease angiogenin (ANG) and RNA modifications in aging, neurodegeneration, and AD development. Cellular functions and important signal pathways depend on numerous protein-coding and non-coding RNAs. In particular, tRNA is of major importance for this project due to its regulatory role in various cellular processes, such as the inhibition of apoptosis. Due to stress response, tRNA must be cleaved by ANG to induce this mechanism. This cleavage results in tRNA-derived fragments such as tiRNAs and tRFs. tiRNAs can inhibit the proapoptotic pathway. Western Blotting was used to determine ANG expression in different cell, animal, and human aging and AD models. In addition to that, tRNA modifications play a crucial role in RNA function and stability. So far, 150 different RNA modifications have been discovered, such as adenosine, cytosine, ribose methylation, or pseudouridine incooperation. The role of tRNA modifications in pathological aging and AD is unknown. Therefore, we used Liquid Chromatography with tandem mass spectrometry (LC-MS/MS) to determine whether tRNA modifications in cell and animal models contribute to mitochondrial defects following the dynamic changes in tRNA modifications pathological process of AD. The results of this thesis revealed age- and gender-dependent dysregulation of ANG and various changes in tRNA modifications in pathological aging and AD.