Serum Exosomes from a Uniquely Defined Early-Adult Cohort Reprogram Endothelial Transcriptomes Linked to Alzheimer's Pathogenesis.
Age-related changes in circulating exosomes are implicated in cerebrovascular aging and the pathogenesis of Alzheimers disease (AD). Neurovascular dysfunction and blood-brain barrier (BBB) breakdown are recognized as early events in AD, often preceding amyloid-{beta} deposition. Primary human brain micro endothelial cells (HBMECs) from a 38-year-old male were treated with exosomes from young (18-25 years) and old (65-72 years) donors. Whole transcriptomic RNA sequencing analysis identified 5,432 differentially expressed genes, which were organized into five transcriptional clusters. Two principal clusters demonstrated reciprocal patterns: 1) exosomes derived from serum of older adult donors (65-72 years) downregulated genes essential for mitochondrial function (e.g., oxidative phosphorylation) and protein synthesis (e.g., ribosomal biogenesis) and 2) upregulating genes linked to inflammation, junctional remodeling, and proliferative signaling. Crucially, subsequent treatment with exosomes derived from serum of young adult donors (18-25 years) reversed these detrimental transcriptomic profiles via restoration of the expression of mitochondrial and ribosomal machinery toward baseline and suppressed the inflammatory and maladaptive proliferative signaling induced by exosomes derived from serum of older adult donors. These findings demonstrate that exosomes derived from serum of young adult donors can counteract detrimental signals of aging at the transcriptional level, reinforcing the cellular architecture underlying BBB integrity. This supports the therapeutic potential of using exosomes derived from serum of young adult donors to reverse endothelial aging and interrupt the early neurovascular dysfunction that contributes to the progression of AD.