Alzheimer’s disease (AD) is characterized by progressive synaptic dysfunction, deterioration of neuronal transmission, and consequently neuronal death. Although there is no treatment for AD, exposure to enriched environment (EE) in mice, as well as physical and mental activity in human subjects have been shown to have a protective effect by slowing the disease’s progression and reducing AD-like cognitive impairment. However, the molecular mechanism of this mitigating effect is still not understood. One of the mechanisms that has recently been shown to be involved in neuronal degeneration is microRNAs (miRNAs) regulation, which act as a post-transcriptional regulators of gene expression. miR-128 has been shown to be significantly altered in individuals with AD and in mice following exposure to EE. Here, we focused on elucidating the possible role of miR-128 in AD pathology and found that miR-128 regulates the expression of two proteins essential for synaptic transmission, SNAP-25, and synaptotagmin1 (Syt1). Clinically relevant, in 5xFAD mouse model for AD, this miRNA’s expression was found as downregulated, resembling the alteration found in the hippocampi of individuals with AD. Interestingly, exposing WT mice to EE also resulted in downregulation of miR-128 expression levels, although EE and AD conditions demonstrate opposing effects on neuronal functioning and synaptic plasticity. We also found that miR-128 expression downregulation in primary hippocampal cultures from 5xFAD mice results in increased neuronal network activity and neuronal excitability. Altogether, our findings place miR-128 as a synaptic player that may contribute to synaptic functioning and plasticity through regulation of synaptic protein expression and function.

阿尔茨海默病 (AD) 的特征是进行性突触功能障碍、神经元传递恶化，从而导致神经元死亡。尽管没有针对 AD 的治疗方法，但小鼠暴露于丰富的环境 (EE) 以及人类受试者的身体和精神活动已被证明通过减缓疾病的进展和减少 AD 样认知障碍而具有保护作用。然而，这种缓解作用的分子机制仍不清楚。最近显示参与神经元变性的机制之一是 microRNA (miRNA) 调节，它充当基因表达的转录后调节剂。已显示 miR-128 在 AD 个体和暴露于 EE 的小鼠中显着改变。这里，我们专注于阐明 miR-128 在 AD 病理学中的可能作用，发现 miR-128 调节突触传递所必需的两种蛋白质 SNAP-25 和 synaptotagmin1 (Syt1) 的表达。临床相关，在 AD 的 5xFAD 小鼠模型中，发现该 miRNA 的表达下调，类似于在 AD 个体的海马中发现的变化。有趣的是，将 WT 小鼠暴露于 EE 也会导致 miR-128 表达水平的下调，尽管 EE 和 AD 条件对神经元功能和突触可塑性表现出相反的影响。我们还发现 5xFAD 小鼠原代海马培养物中 miR-128 表达下调导致神经元网络活动和神经元兴奋性增加。共，