Cognitive impairment in learning, memory, and executive function occurs in normal aging even in the absence of Alzheimer’s disease (AD). While neurons do not degenerate in humans or monkeys free of AD, there are structural changes including synapse loss and dendritic atrophy, especially in the dorsolateral prefrontal cortex (dlPFC), and these correlate with cognitive age-related impairment. Developmental studies revealed activity-dependent neuronal properties that lead to synapse remodeling by microglia. Microglia-mediated phagocytosis that may eliminate synapses is regulated by immune “eat me” and “don’t eat me” signaling proteins in an activity-dependent manner, so that less active synapses are eliminated. Whether this process contributes to age-related synapse loss remains unknown. The present study used a rhesus monkey model of normal aging to investigate the balance between the “eat me” signal, complement component C1q, and the “don’t eat me” signal, transmembrane glycoprotein CD47, relative to age-related synapse loss in dlPFC Area 46. Results showed an age-related elevation of C1q and reduction of CD47 at PSD95+ synapses that is associated with cognitive impairment. Additionally, reduced neuronal CD47 RNA expression was found, indicating that aged neurons were less able to produce the protective signal CD47. Interestingly, microglia do not show the hypertrophic morphology indicative of phagocytic activity. These findings suggest that in the aging brain, changes in the balance of immunologic proteins give microglia instructions favoring synapse elimination of less active synapses, but this may occur by a process other than classic phagocytosis such as trogocytosis.

即使没有阿尔茨海默病 （AD），正常衰老也会发生学习、记忆和执行功能的认知障碍。虽然人类或猴子的神经元不会在没有 AD 的情况下退化，但存在结构变化，包括突触丢失和树突萎缩，尤其是在背外侧前额叶皮层 （dlPFC），这些变化与认知年龄相关的障碍相关。发育研究揭示了导致小胶质细胞突触重塑的活动依赖性神经元特性。可能消除突触的小胶质细胞介导的吞噬作用以活动依赖性方式受到免疫“吃我”和“不吃我”信号蛋白的调节，从而消除不太活跃的突触。这个过程是否会导致与年龄相关的突触丢失仍然未知。本研究使用正常衰老的恒河猴模型来研究“吃我”信号（补体成分 C1q）和“不要吃我”信号（跨膜糖蛋白 CD47）相对于 dlPFC Area 46 中年龄相关突触丢失之间的平衡。结果显示与年龄相关的 C1q 升高和 PSD95 + 突触处 CD47 的减少，这与认知障碍有关。此外，发现神经元 CD47 RNA 表达降低，表明衰老神经元产生保护信号 CD47 的能力较差。有趣的是，小胶质细胞没有显示出指示吞噬活性的肥大形态。这些发现表明，在衰老的大脑中，免疫蛋白平衡的变化为小胶质细胞提供了有利于突触消除不太活跃的突触的指令，但这可能是通过经典吞噬作用（如胞吞作用）以外的过程发生的。