Department of Pharmacy, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong 510630, China.
Department of Pharmacy, Minzu Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi 530001, China.
Behav Brain Res. 2021 Jan 15;397:112939. doi: 10.1016/j.bbr.2020.112939. Epub 2020 Sep 28.
With the lengthening of the human lifespan, an increasing proportion of the population is subject to age-related cognitive impairments, making it important to investigate ways to confront the effects of aging. Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor that is expressed mainly on the surfaces of microglia. Previous studies have found a significant positive correlation between age and TREM2 levels. An increased concentration of soluble TREM2 in cerebrospinal fluid was also found in Alzheimer's disease (AD) patients. Although TREM2 is more highly expressed in microglia than in astrocytes, little attention has been focused on astrocytic TREM2, and the precise role of astrocytic TREM2 in the aging process remains unknown. In this study, we injected TREM2 shRNA into the hippocampal CA1 region to specifically knock down the expression of this protein in astrocytes. We found that TREM2 shRNA injection can improve learning and memory ability in elderly mice, as demonstrated by improved learning ability and memory performance in the Morris water maze (MWM) test, an increased freezing duration in the contextual fear conditioning test, a higher preference ratio in the novel object recognition (NOR) test and a higher alternation rate in the T-maze test. Knocking down astrocytic TREM2 can also rescue impaired long-term potentiation (LTP) induction in the hippocampal CA1 of elderly mice through a presynaptic mechanism. Our results suggest that decreased astrocytic TREM2 levels have beneficial effects on learning and memory ability in elderly mice, which may provide new insight into the pathological mechanism and potential targets of age-related dementia.
随着人类寿命的延长，越来越多的人受到与年龄相关的认知障碍的影响，因此研究如何应对衰老的影响变得尤为重要。髓样细胞触发受体 2（TREM2）是一种先天免疫受体，主要表达在小胶质细胞表面。先前的研究发现，年龄与 TREM2 水平呈显著正相关。阿尔茨海默病（AD）患者的脑脊液中也发现可溶性 TREM2 浓度增加。尽管 TREM2 在小胶质细胞中的表达高于星形胶质细胞，但对星形胶质细胞 TREM2 的关注较少，星形胶质细胞 TREM2 在衰老过程中的精确作用仍不清楚。在这项研究中，我们将 TREM2 shRNA 注射到海马 CA1 区，以特异性敲低星形胶质细胞中该蛋白的表达。我们发现，TREM2 shRNA 注射可以改善老年小鼠的学习和记忆能力，表现在 Morris 水迷宫（MWM）测试中学习能力提高，记忆表现改善，情境恐惧条件测试中冻结时间延长，新物体识别（NOR）测试中偏好比增加，T 迷宫测试中交替率增加。敲低星形胶质细胞 TREM2 还可以通过突触前机制挽救老年小鼠海马 CA1 区长期增强（LTP）诱导受损。我们的结果表明，降低星形胶质细胞 TREM2 水平对老年小鼠的学习和记忆能力有有益的影响，这可能为与年龄相关的痴呆的病理机制和潜在靶点提供新的见解。
