Amyloid β Protein Aggravates Neuronal Senescence and Cognitive Deficits in 5XFAD Mouse Model of Alzheimer's Disease.

Amyloid β (Aβ) has been established as a key factor for the pathological changes in the brains of patients with Alzheimer's disease (AD), and cellular senescence is closely associated with aging and cognitive impairment. However, it remains blurred whether, in the AD brains, Aβ accelerates the neuronal senescence and whether this senescence, in turn, impairs the cognitive function. This study aimed to explore the expression of senescence-associated genes in the hippocampal tissue from young to aged 5XFAD mice and their age-matched wild type (WT) mice to determine whether senescent neurons are present in the transgenic AD mouse model. The 5XFAD mice and age-matched wild type mice, both raised from 1 to 18 months, were enrolled in the study. The senescence-associated genes in the hippocampus were analyzed and differentially expressed genes (DEGs) were screened by quantitative real-time polymerase chain reaction. Cognitive performance of the mice was evaluated by Y-maze and Morris water maze tests. Oligomeric Aβ (oAβ) (1–42) was applied to culture primary neurons to simulate the in vivo manifestation. Aging-related proteins were detected by Western blotting analysis and immunofluorescence. In 5XFAD mice, of all the DEGs, the senescence-associated marker p16 was most significantly increased, even at the early age. It was mainly localized in neurons, with a marginal expression in astrocytes (labeled as glutamine synthetase), nil expression in activated microglia (labeled as Iba1), and negatively correlated with the spatial cognitive impairments of 5XFAD mice. oAβ (1–42) induced the production of senescence-related protein p16, but not p53 in vitro, which was in line with the in vivo manifestation. oAβ-accelerated neuronal senescence may be associated with the cognitive impairment in 5XFAD mice. Senescence-associated marker p16 can serve as an indicator to estimate the cognitive prognosis for AD population.

淀粉样β蛋白（Aβ）已被确定为阿尔茨海默病（AD）患者大脑病理变化的关键因素，细胞衰老与衰老和认知障碍密切相关。然而，在AD大脑中，Aβ是否加速神经元衰老以及这种衰老是否反过来损害认知功能仍不清楚。本研究旨在探讨从幼年到老年的5XFAD小鼠及其年龄匹配的野生型（WT）小鼠海马组织中衰老相关基因的表达，以确定转基因AD小鼠模型中是否存在衰老神经元。 将1至18个月的5XFAD小鼠和年龄匹配的野生型小鼠纳入研究。通过实时定量聚合酶链反应分析海马中的衰老相关基因并筛选差异表达基因（DEGs）。通过Y迷宫和莫里斯水迷宫测试评估小鼠的认知能力。将寡聚Aβ（oAβ）（1 - 42）用于培养原代神经元以模拟体内表现。通过蛋白质印迹分析和免疫荧光检测衰老相关蛋白。 在5XFAD小鼠中，在所有差异表达基因中，衰老相关标志物p16即使在早期也显著增加。它主要定位于神经元，在星形胶质细胞（标记为谷氨酰胺合成酶）中少量表达，在活化的小胶质细胞（标记为Iba1）中无表达，并且与5XFAD小鼠的空间认知障碍呈负相关。oAβ（1 - 42）在体外诱导衰老相关蛋白p16的产生，但不诱导p53的产生，这与体内表现一致。 oAβ加速的神经元衰老可能与5XFAD小鼠的认知障碍有关。衰老相关标志物p16可作为评估AD人群认知预后的指标。