Alzheimer39;s disease (AD) is a neurodegenerative disorder clinically characterized by progressive memory loss and cognitive decline. Pathological hallmarks of the disease are the formation of amyloid plaques and neurofibrillary tangles. Several research has demonstrated that AD-related pathological changes occur long before clinical symptoms are manifested. Thus, it is crucial to establish an accurate diagnosis at an early stage, particularly for individuals aged 60 years and above. Biomarkers serve as vital tools for AD diagnosis, monitoring, early detection, therapeutic intervention, and preventing inaccurate diagnoses. Still, there are no robust tools or biomarkers that can provide precise information for the diagnosis of AD. tRNA-derived fragments (tRFs) are a distinctive type of small non-coding RNAs produced from tRNAs via nucleases Dicer and Angiogenin. tRFs can regulate biological functions such as translation and transcription. Recently, there has been much attention drawn to the previously unexplored connection between tRFs and neurodegenerative disorders. Extracellular vesicles (EVs) are vesicles with lipid membranes and contain numerous different molecules, such as nucleic acids, proteins, and lipids. Within their cargo contents, EVs contribute to development, cell growth, and survival, intercellular communication, and waste disposal, but also to disease pathogenesis. Just like all other cell types, neurons also secrete extracellular vesicles, and neuron-derived extracellular vesicles (NDEVs) may contain distinctive cargoes. In this study, we profiled the tRF content of neuron-derived extracellular vesicles (NDEVs) of AD patients and healthy controls (HCs) with next-generation sequencing. We demonstrated that six tRFs (ProAGG, GluTTC, LysCTT, LeuAAG, SerAGA, ValCAC) were differentially expressed in NDEVs of AD patients compared to HCs. Further, we confirmed those tRFs on a considerably larger population with the RT-qPCR method. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes annotation also indicated that these are enriched in various neuron and brain-related categories; for example, axogenesis (GO:0007409), regulation of nervous system development (GO:0051960), and regulation of neuron projection development (GO:0010975). Taken together, our results indicate that dysregulated tRFs have the potential to serve as a biomarker for AD in future investigations.

The 7th Venusberg Meeting on Neuroinflammation, Luxembourg, Luxembourg, 11 - 13 May 2023, pp.1

Alzheimer's disease (AD) is a neurodegenerative disorder clinically characterized by progressive

memory loss and cognitive decline. Pathological hallmarks of the disease are the formation of

amyloid plaques and neurofibrillary tangles. Several research has demonstrated that AD-related

pathological changes occur long before clinical symptoms are manifested. Thus, it is crucial to

establish an accurate diagnosis at an early stage, particularly for individuals aged 60 years and above.

Biomarkers serve as vital tools for AD diagnosis, monitoring, early detection, therapeutic

intervention, and preventing inaccurate diagnoses. Still, there are no robust tools or biomarkers that

can provide precise information for the diagnosis of AD. tRNA-derived fragments (tRFs) are a

distinctive type of small non-coding RNAs produced from tRNAs via nucleases Dicer and

Angiogenin. tRFs can regulate biological functions such as translation and transcription. Recently,

there has been much attention drawn to the previously unexplored connection between tRFs and

neurodegenerative disorders. Extracellular vesicles (EVs) are vesicles with lipid membranes and

contain numerous different molecules, such as nucleic acids, proteins, and lipids. Within their cargo

contents, EVs contribute to development, cell growth, and survival, intercellular communication, and

waste disposal, but also to disease pathogenesis. Just like all other cell types, neurons also secrete

extracellular vesicles, and neuron-derived extracellular vesicles (NDEVs) may contain distinctive

cargoes. In this study, we profiled the tRF content of neuron-derived extracellular vesicles (NDEVs)

of AD patients and healthy controls (HCs) with next-generation sequencing. We demonstrated that six

tRFs (ProAGG, GluTTC, LysCTT, LeuAAG, SerAGA, ValCAC) were differentially expressed in

NDEVs of AD patients compared to HCs. Further, we confirmed those tRFs on a considerably larger

population with the RT-qPCR method. Gene Ontology and Kyoto Encyclopedia of Genes and

Genomes annotation also indicated that these are enriched in various neuron and brain-related

categories; for example, axogenesis (GO:0007409), regulation of nervous system development

(GO:0051960), and regulation of neuron projection development (GO:0010975). Taken together, our

results indicate that dysregulated tRFs have the potential to serve as a biomarker for AD in future

investigations.