Landon Benjamin, Subasinghe Kumudu, Sumien Nathalie, Phillips Nicole
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, United States of America.
Department of Microbiology Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, United States of America.
Exp Gerontol. 2025 Jun 1;204:112745. doi: 10.1016/j.exger.2025.112745. Epub 2025 Apr 1.
Alzheimer's Disease (AD) is the most prevalent form of dementia and one of the leading causes of death in the United States, and despite our best efforts and recent advancements, a treatment that stops or substantially slows its progression has remained elusive. Small extracellular vesicles (sEVs), hold the potential to alleviate some of the common issues in the field by serving to better differentiate AD and non-AD individuals. These vesicles could provide insights into therapeutic targets, and potentially an avenue towards early detection. We compared the sEV cargo profiles of AD and non-AD brains (n = 6) and identified significant differences in both the micro RNA (miRNA) and Piwi-interacting RNA (piRNA) cargo through sEV isolation from temporal cortex tissue, followed by small RNA sequencing, and differential expression analysis. Differentially expressed miRNAs targeting systems relevant to AD included miR-206, miR-4516, miR-219a-5p, and miR-486-5p. Significant piRNAs included piR-6,565,525, piR-2,947,194, piR-7,181,973, and piR-7,326,987. These targets warrant further study for their potential role in the progression of AD pathology by dysregulating cellular activity; additionally, future large-scale studies of neuronal sEV miRNA profiles may facilitate the development of diagnostic tools which can aid in clinical trial design and recruitment. Longitudinal analysis of sEV data, perhaps accessible through plasma surveyance, will help determine at what point these miRNA and/or piRNA profiles begin to diverge between AD and non-AD individuals.
阿尔茨海默病（AD）是最常见的痴呆形式，也是美国主要的死亡原因之一。尽管我们已竭尽全力且取得了一些进展，但能阻止或显著减缓其进展的治疗方法仍未找到。小型细胞外囊泡（sEVs）有潜力通过更好地区分AD患者和非AD患者来缓解该领域的一些常见问题。这些囊泡可为治疗靶点提供见解，并有可能成为早期检测的途径。我们比较了AD和非AD大脑（n = 6）的sEV货物谱，通过从颞叶皮质组织中分离sEV，然后进行小RNA测序和差异表达分析，确定了微小RNA（miRNA）和Piwi相互作用RNA（piRNA）货物中的显著差异。与AD相关的差异表达miRNA靶向系统包括miR-206、miR-4516、miR-219a-5p和miR-486-5p。显著的piRNA包括piR-6,565,525、piR-2,947,194、piR-7,181,973和piR-7,326,987。这些靶点因通过调节细胞活性失调而在AD病理进展中的潜在作用值得进一步研究；此外，未来对神经元sEV miRNA谱的大规模研究可能会促进诊断工具的开发，这有助于临床试验的设计和招募。对sEV数据的纵向分析，或许可通过血浆监测获得，将有助于确定这些miRNA和/或piRNA谱在AD和非AD个体之间何时开始出现差异。
