Abortive transcripts in exosomes - A potential biomarker for Alzheimer’s disease

Diagnosis of Alzheimer's disease (AD) relies on invasive cerebrospinal fluid analysis or costly neuroimaging, underscoring the need for minimally invasive blood-based biomarkers for early detection. Exosomes, promising biomarker carriers, are unexplored for ultra-short RNA species like abortive transcripts (ATs). We investigated whether 8-nucleotide ATs are selectively packaged into exosomes to reflect brain transcriptional dysregulation in AD. Using a transgenic AD mouse model and Aβ-stimulated BV2 microglia coupled with Base-Stacking Hybridization Assisted Ligation (BSHAL), we detected significant dysregulation of ATs from AD-relevant genes (Nefl, Bace1, Tyrobp, Ccl2, Pf4) in brain tissue; specifically, Bace1, Tyrobp, and Pf4 ATs showed robust increases (2.21-fold to 17.50-fold). These dysregulated AT signatures were mirrored in peripheral blood exosomes: Bace1, Tyrobp, and Pf4 ATs increased 10.58-, 38.72-, and 11.63-fold, respectively. Aβ-activated microglia demonstrated exosome-specific enrichment of ATs, particularly Pf4 ATs (~3510-fold increase), confirming active exosomal packaging. Exosomal ATs confer cell-type specificity for central nervous system pathology, lipid bilayer-enhanced stability, and sensitivity to transcriptional changes preceding pathological aggregation. Our findings, obtained in a transgenic mouse model and an in vitro microglial system, establish exosomal ATs as a novel class of blood-based biomarkers with potential for early AD diagnosis, pending validation in human cohorts.