全基因组分析海马转移 RNA 衍生的小 RNA 鉴定补肾填髓方治疗阿尔茨海默病的新潜在治疗靶点。
Genome-wide analysis of hippocampal transfer RNA-derived small RNAs identifies new potential therapeutic targets of Bushen Tiansui formula against Alzheimer's disease.
机构信息
Department of Integrated Traditional Chinese & Western Medicine, the Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China.
Department of Integrated Traditional Chinese & Western Medicine, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China.
出版信息
J Integr Med. 2021 Mar;19(2):135-143. doi: 10.1016/j.joim.2020.12.005. Epub 2020 Dec 5.
OBJECTIVE
Bushen Tiansui formula (BSTSF), a traditional Chinese medicine prescription, has been widely used to treat Alzheimer's disease (AD). However, the mechanisms underlying its effects remain largely unknown. In this study, a rat AD model was used to study the effects of BSTSF on cognitive performance and expression of transfer RNA-derived small RNAs (tsRNAs) in the hippocampus, to determine whether treatment of AD with BSTSF could regulate the expression of tsRNAs, a novel small non-coding RNA.
METHODS
To generate a validated AD model, oligomeric amyloid-β (Aβ) was injected intracerebroventricularly into rats. The Morris water maze (MWM) test was used to evaluate rat cognitive performance, and tsRNA-sequencing was conducted to examine tsRNA expression in the rat hippocampus. Potential targets were validated by quantitative real-time polymerase chain reaction (qRT-PCR). Bioinformatic analyses were conducted to investigate the biological function of candidate tsRNAs.
RESULTS
The learning and memory deficits of Aβ-induced AD rats, assessed by MWM tests, were clearly ameliorated by BSTSF treatment. A total of 387 tsRNAs were detected in the rat hippocampus. Among them, 13 were significantly dysregulated in AD rats compared with sham control rats, while 57 were markedly altered by BSTSF treatment, relative to untreated AD rats (fold change ≥ 2 and P < 0.05). Moreover, six BSTSF treatment-related tsRNAs were identified and validated by qRT-PCR. Bioinformatic analyses indicated that the six treatment-related tsRNAs had potential therapeutic roles, via multiple signaling pathways and Gene Ontology biological functions, including cyclic adenosine monophosphate and retrograde endocannabinoid signaling.
CONCLUSION
This study identified a previously uncharacterized mechanism underlying the effects of BSTSF in alleviating the learning and memory deficits in Aβ-induced AD rats, demonstrating that tsRNAs are potential therapeutic targets of BSTSF in the treatment of AD.
目的
补肾填髓方（BSTSF）是一种中药方剂，已广泛用于治疗阿尔茨海默病（AD）。然而，其作用机制仍知之甚少。本研究采用 AD 大鼠模型，研究 BSTSF 对大鼠认知功能和海马组织转移 RNA 衍生的小 RNA（tsRNA）表达的影响，以确定 BSTSF 治疗 AD 是否能调节 tsRNA 的表达，这是一种新型的小非编码 RNA。
方法
采用寡聚淀粉样β（Aβ）侧脑室注射法制备 AD 大鼠模型。利用 Morris 水迷宫（MWM）测试评估大鼠的认知功能，通过 tsRNA 测序检测大鼠海马组织中 tsRNA 的表达。采用实时定量聚合酶链反应（qRT-PCR）验证潜在靶点。通过生物信息学分析探讨候选 tsRNA 的生物学功能。
结果
MWM 测试结果表明，BSTSF 治疗可明显改善 Aβ诱导的 AD 大鼠的学习记忆障碍。在大鼠海马组织中共检测到 387 种 tsRNA，其中 13 种在 AD 大鼠中与 sham 对照组相比明显失调，而 57 种在未经治疗的 AD 大鼠中与 BSTSF 治疗组相比明显改变（倍数变化≥2，P<0.05）。此外，通过 qRT-PCR 验证了 6 种与 BSTSF 治疗相关的 tsRNA。生物信息学分析表明，这 6 种治疗相关的 tsRNA 通过多种信号通路和基因本体生物功能（包括环磷酸腺苷和逆行内源性大麻素信号）发挥潜在的治疗作用。
结论
本研究发现了 BSTSF 缓解 Aβ诱导的 AD 大鼠学习记忆障碍的作用机制，表明 tsRNA 是 BSTSF 治疗 AD 的潜在治疗靶点。
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