Changes of tRNA-Derived Fragments by Alzheimer's Disease in Cerebrospinal Fluid and Blood Serum.
Changes of tRNA-Derived Fragments by Alzheimer's Disease in Cerebrospinal Fluid and Blood Serum.
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DOI：
10.3233/jad-230412
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发表时间：
2023-11
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通讯作者：
Wenzhe Wu;Audrey Shen;Inhan Lee;Ernesto G Miranda-Morales;Heidi Spratt;Miguel A Pappolla;Xiang Fang;Xiaoyong Bao
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作者：
Wenzhe Wu;Audrey Shen;Inhan Lee;Ernesto G Miranda-Morales;Heidi Spratt;Miguel A Pappolla;Xiang Fang;Xiaoyong Bao
阿尔茨海默病（AD）是最常见的痴呆类型，影响65岁以上的个体。AD也是一种多因素疾病，疾病机制的特征不完全，疾病修饰疗法的效果甚微。生物标志物的签名可以阐明诊断，疾病机制和治疗靶点的发展。tRNA衍生的RNA片段（tRFs），最近发现的一个小的非编码RNA家族，已被发现在人类AD海马组织中显着增强。然而，tRFs是否在体液中变化尚不清楚。目的探讨AD对体液中tRFs的影响。我们首先使用T4多核苷酸激酶-RNA-seq，一种改良的下一代测序技术，鉴定人脑脊液和血清样本中可检测的tRFs。然后使用tRF qRT-PCR比较来自对照、AD和轻度认知障碍患者的这些液体中的可检测tRF。还通过检查tRF响应于蛋白质消化或外来体裂解的变化来研究tRF在血清中的稳定性。结果AD对脑脊液和血清中tRF 5-ProAGG表达均有影响。AD影响的血清tRF 5-ProAGG显示与AD分期相关。还通过计算算法预测了海马中tRF 5-ProAGG的推定靶点，其中一些靶点经过实验验证，其中一个靶点即使使用小样本也与tRF 5-ProAGG呈负相关。结论：tRF 5-ProAGG具有作为AD生物标志物的潜力，并可能在疾病进展中发挥作用。
BACKGROUND Alzheimer's disease (AD) is the most common type of dementia, affecting individuals over 65. AD is also a multifactorial disease, with disease mechanisms incompletely characterized, and disease-modifying therapies are marginally effective. Biomarker signatures may shed light on the diagnosis, disease mechanisms, and the development of therapeutic targets. tRNA-derived RNA fragments (tRFs), a family of recently discovered small non-coding RNAs, have been found to be significantly enhanced in human AD hippocampus tissues. However, whether tRFs change in body fluids is unknown. OBJECTIVE To investigate whether tRFs in body fluids are impacted by AD. METHODS We first used T4 polynucleotide kinase-RNA-seq, a modified next-generation sequencing technique, to identify detectable tRFs in human cerebrospinal fluid and serum samples. The detectable tRFs were then compared in these fluids from control, AD, and mild cognitive impairment patients using tRF qRT-PCR. The stability of tRFs in serum was also investigated by checking the change in tRFs in response to protein digestion or exosome lysis. RESULTS Among various tRFs, tRF5-ProAGG seemed to be impacted by AD in both cerebrospinal fluid and serum. AD-impacted serum tRF5-ProAGG showed a correlation with the AD stage. Putative targets of tRF5-ProAGG in the hippocampus were also predicted by a computational algorithm, with some targets being validated experimentally and one of them being in a negative correlation with tRF5-ProAGG even using a small size of samples. CONCLUSIONS tRF5-ProAGG showed the potential as an AD biomarker and may play a role in disease progression.