RhoA-LIMK Signaling Axis Reveals Rostral-Caudal Plane and Spatial Dysregulation in the Brain of Alzheimer's Disease Mouse Models.
RhoA-LIMK Signaling Axis Reveals Rostral-Caudal Plane and Spatial Dysregulation in the Brain of Alzheimer's Disease Mouse Models.
复制标题
DOI：
10.3233/jad-230408
复制
发表时间：
2023-09
期刊：
影响因子：
--
通讯作者：
Shayan Nik Akhtar;Quanlong Lu
中科院分区：
文献类型：
--
作者：
Shayan Nik Akhtar;Quanlong Lu
RhoA信号在阿尔茨海默病（AD）中被广泛报道失调，但其治疗靶点显示出不同的结果。我们假设RhoA和LIMK的激活和失活状态在皮层和海马沿喙尾侧的亚区是不同的。目的：我们旨在阐明与AD相关的平面和空间依赖性RhoA信号。方法应用识别RhoA失活状态（S188磷酸化）的pRhoA抗体和识别LIMK活性状态（T508磷酸化）的pLIMK抗体，研究野生型（WT）和三重转基因AD （3xTg-AD）小鼠模型中的RhoA信号转导。我们制备了整个小鼠大脑从吻侧到尾侧冠状面连续切片，并用pRhoA和pLIMK抗体进行免疫荧光染色。结果pRhoA和pLIMK均可诱导表达模式从吻侧向尾侧转移。此外，pRhoA在细胞核和细胞质之间表现出动态再分布。pLIMK未表现出细胞核和细胞质的重新分布，但表达水平从吻侧到尾侧发生了变化。在3xTg-AD小鼠海马部分平面上，pRhoA在皮层的表达呈上升趋势，在齿状回的表达呈下降趋势。pLIMK在3xTg-AD小鼠海马皮层呈下降趋势，在齿状回呈上升趋势。结论：RhoA激活在人和小鼠AD大脑中均存在失调，RhoA- limk信号轴沿喙尾平面维度显示空间失调。
BACKGROUND RhoA signaling is widely reported to be dysregulated in Alzheimer's disease (AD), but its therapeutic targeting demonstrated mixed outcomes. We hypothesize that the activation and inactivation states of RhoA and LIMK are different in the cortex and in subregions of hippocampus along the rostral-caudal dimensions. OBJECTIVE We intended to elucidate the plane and spatial dependent RhoA signaling in association with AD. METHODS We applied antibody pRhoA that recognizes an inactive state of RhoA (S188 phosphorylation) and antibody pLIMK against an active state of LIMK (T508 phosphorylation) to investigate RhoA signaling in wildtype (WT) and triple transgenic AD (3xTg-AD) mouse model. We prepared serial sections from the rostral to caudal coronal planes of the entire mouse brain followed by immunofluorescence staining with pRhoA and pLIMK antibodies. RESULTS Both pRhoA and pLIMK elicited a shift of expression pattern from rostral to caudal planes. Additionally, pRhoA demonstrated dynamic redistribution between the nucleus and cytoplasm. pLIMK did not show such nucleus and cytoplasm redistribution but the expression level was changed from rostral to caudal planes. At some planes, pRhoA showed an increasing trend in expression in the cortex but a decreasing trend in the dentate gyrus of the 3xTg-AD mouse hippocampus. pLIMK tends to decrease in the cortex but increase in the dentate gyrus of 3xTg-AD mouse hippocampus. CONCLUSIONS RhoA activation is dysregulated in both human and mouse AD brains, and the RhoA-LIMK signaling axis reveals spatial dysregulation along the rostral-caudal plane dimensions.