Role of tRNA-Derived Fragments and Their Modifications in the Pathogenesis and Treatment of Alzheimer's Disease.

Transfer RNAs (tRNAs), an essential class of noncoding RNAs, have recently emerged as a hotspot in the study of neurodegenerative diseases. The biological function of tRNA depends on precise processing and complex chemical modifications. During processing, tRNAs not only produce functional tRNAs used in protein synthesis but also generate tRNA-derived fragments (tRFs) that play roles in gene expression regulation. In addition, a series of chemical modifications, such as methylation, occur on the bases or phosphate backbone of tRNAs. In the progression of Alzheimer's disease (AD), researchers have observed significant changes in both the abundance and modification patterns of tRFs. This review summarizes the roles and regulatory mechanisms of tRFs and their chemical modifications in AD and integrates findings on potential tRF target genes to provide new insights into the pathogenesis of AD. Evidence suggests that distinct tRFs regulate gene expression through complementary interactions with specific targets. For example, AS-tDR-011389 upregulates CaMK2N1 expression by binding to its 3' untranslated region, suggesting that it may modulate calcium homeostasis in AD because CaMK2N1 is known to be involved in calcium signaling. Furthermore, tRF5-ProAGG was shown to target SV2B through predicted tRF5-mRNA pairing and qRT-PCR validation. Dysregulation of SV2B expression indicates that tRF5-ProAGG may influence synaptic vesicle trafficking and synaptic plasticity, thereby affecting neurotransmitter release and synaptic transmission in AD. Additionally, widespread reductions in cytoplasmic and mitochondrial tRNA methylation, accompanied by decreased expression of modification enzymes, have been observed in 5XFAD mice. These aberrant modifications may impair tRNA function, disrupt gene expression and protein translation, and ultimately contribute to AD progression.