Alzheimer’s disease (AD) is the most common form of dementia, affecting approximately 6.5 million Americans age 65 or older. AD is characterized by increased cognitive impairment and treatment options available provide minimal disease attenuation. Additionally, diagnostic methods for AD are not conclusive with definitive diagnoses requiring postmortem brain evaluations. Therefore, miRNAs, a class of small, non-coding RNAs, have garnered attention for their ability to regulate a variety of mRNAs and their potential to serve as both therapeutic targets and biomarkers of AD. Several miRNAs have already been implicated with AD and have been found to directly target genes associated with AD pathology. The APP/PS1 mice is an AD model that expresses the human mutated form of the amyloid precursor protein (APP) and presenilin-1 (PS1) genes. In a previous study, it was identified that crossing long-living growth hormone (GH)-deficient Ames dwarf (df/df) mice with APP/PS1 mice provided protection from AD through a reduction in IGF-1, amyloid-β (Aβ) deposition, and gliosis. Hence, we hypothesized that changes in the expression of miRNAs associated with AD mediated such benefits. To test this hypothesis, we sequenced miRNAs in hippocampi of df/df, wild type (+ / +), df/ + /APP/PS1 (phenotypically normal APP/PS1), and df/df/APP/PS1 mice. Results of this study demonstrated significantly upregulated and downregulated miRNAs between df/df/APP/PS1 and df/ + /APP/PS1 mice that suggest the df/df mutation provides protection from AD progression. Additionally, changes in miRNA expression with age were identified in both df/df and wild-type mice as well as df/df/APP/PS1 and APP/PS1 mice, with predictive functional roles in the Pi3k-AKT/mTOR/FOXO pathways potentially contributing to disease pathogenesis.

阿尔茨海默病 (AD) 是最常见的痴呆症，影响大约 650 万 65 岁或以上的美国人。AD 的特点是认知障碍加重，而可用的治疗方案可将疾病减弱程度降至最低。此外，AD 的诊断方法并不具有决定性，需要进行死后大脑评估才能做出明确诊断。因此，miRNA 作为一类小非编码 RNA，因其调节多种 mRNA 的能力及其作为 AD 治疗靶点和生物标志物的潜力而受到关注。一些 miRNA 已经与 AD 相关，并且被发现直接靶向与 AD 病理相关的基因。APP/PS1 小鼠是一种 AD 模型，表达淀粉样前体蛋白 (APP) 和早老素-1 (PS1) 基因的人类突变形式。在之前的一项研究中，发现将长寿生长激素 (GH) 缺陷型 Ames 侏儒 (df/df) 小鼠与 APP/PS1 小鼠杂交，通过减少 IGF-1、淀粉样蛋白 -β (Aβ) 来预防 AD 的发生。 ）沉积和神经胶质增生。因此，我们假设与 AD 相关的 miRNA 表达的变化介导了这种益处。为了检验这一假设，我们对 df/df、野生型 (+/+)、df/ + /APP/PS1（表型正常 APP/PS1）和 df/df/APP/PS1 小鼠的海马中的 miRNA 进行了测序。这项研究的结果表明，df/df/APP/PS1 和 df/ + /APP/PS1 小鼠之间的 miRNA 显着上调和下调，这表明 df/df 突变可以防止 AD 进展。此外，在 df/df 和野生型小鼠以及 df/df/APP/PS1 和 APP/PS1 小鼠中都发现了 miRNA 表达随年龄的变化，在 Pi3k-AKT/mTOR/FOXO 通路中具有预测功能作用可能有助于疾病的发病机制。