Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon 34141, Korea.
Department of Health Sciences, The Graduate School of Dong-A University, Dong-A University, Busan 49315, Korea.
Int J Mol Sci. 2020 Dec 13;21(24):9482. doi: 10.3390/ijms21249482.
Alzheimer's disease (AD) is a neurodegenerative disease characterized by neurological dysfunction, including memory impairment, attributed to the accumulation of amyloid β (Aβ) in the brain. Although several studies reported possible mechanisms involved in Aβ pathology, much remains unknown. Previous findings suggested that a protein regulated in development and DNA damage response 1 (REDD1), a stress-coping regulator, is an Aβ-responsive gene involved in Aβ cytotoxicity. However, we still do not know how Aβ increases the level of REDD1 and whether REDD1 mediates Aβ-induced synaptic dysfunction. To elucidate this, we examined the effect of Aβ on REDD1-expression using acute hippocampal slices from mice, and the effect of REDD1 short hairpin RNA (shRNA) on Aβ-induced synaptic dysfunction. Lastly, we observed the effect of REDD1 shRNA on memory deficit in an AD-like mouse model. Through the experiments, we found that Aβ-incubated acute hippocampal slices showed increased REDD1 levels. Moreover, Aβ injection into the lateral ventricle increased REDD1 levels in the hippocampus. Anisomycin, but not actinomycin D, blocked Aβ-induced increase in REDD1 levels in the acute hippocampal slices, suggesting that Aβ may increase REDD1 translation rather than transcription. Aβ activated Fyn/ERK/S6 cascade, and inhibitors for Fyn/ERK/S6 or mGluR5 blocked Aβ-induced REDD1 upregulation. REDD1 inducer, a transcriptional activator, and Aβ blocked synaptic plasticity in the acute hippocampal slices. REDD1 inducer inhibited mTOR/Akt signaling. REDD1 shRNA blocked Aβ-induced synaptic deficits. REDD1 shRNA also blocked Aβ-induced memory deficits in passive-avoidance and object-recognition tests. Collectively, these results demonstrate that REDD1 participates in Aβ pathology and could be a target for AD therapy.
阿尔茨海默病（AD）是一种神经退行性疾病，其特征为神经功能障碍，包括记忆障碍，这归因于大脑中淀粉样β（Aβ）的积累。尽管有几项研究报道了可能涉及 Aβ病理学的机制，但仍有许多未知之处。先前的研究结果表明，发育和 DNA 损伤反应 1（REDD1）调节剂是一种 Aβ反应性基因，参与 Aβ细胞毒性。然而，我们仍然不知道 Aβ如何增加 REDD1 的水平，以及 REDD1 是否介导 Aβ诱导的突触功能障碍。为了阐明这一点，我们使用来自小鼠的急性海马切片检查了 Aβ对 REDD1 表达的影响，以及 REDD1 短发夹 RNA（shRNA）对 Aβ诱导的突触功能障碍的影响。最后，我们观察了 REDD1 shRNA 对 AD 样小鼠模型中记忆缺陷的影响。通过实验，我们发现 Aβ孵育的急性海马切片显示 REDD1 水平升高。此外，向侧脑室注射 Aβ会增加海马中的 REDD1 水平。放线菌酮而不是 Actinomycin D 阻断了急性海马切片中 Aβ诱导的 REDD1 水平升高，表明 Aβ可能增加 REDD1 的翻译而不是转录。Aβ激活了 Fyn/ERK/S6 级联反应，并且 Fyn/ERK/S6 或 mGluR5 的抑制剂阻断了 Aβ诱导的 REDD1 上调。REDD1 诱导剂，一种转录激活剂，和 Aβ阻断了急性海马切片中的突触可塑性。REDD1 诱导剂抑制了 mTOR/Akt 信号。REDD1 shRNA 阻断了 Aβ诱导的突触缺陷。REDD1 shRNA 还阻断了 Aβ诱导的被动回避和物体识别测试中的记忆缺陷。总之，这些结果表明 REDD1 参与了 Aβ 病理学，并且可能是 AD 治疗的靶点。
