Stanford University School of Medicine, Department of Neurobiology, Stanford, California 94305-5345, USA.
J Neurosci. 2013 Aug 14;33(33):13460-74. doi: 10.1523/JNEUROSCI.1333-13.2013.
The decline of cognitive function has emerged as one of the greatest health threats of old age. Age-related cognitive decline is caused by an impacted neuronal circuitry, yet the molecular mechanisms responsible are unknown. C1q, the initiating protein of the classical complement cascade and powerful effector of the peripheral immune response, mediates synapse elimination in the developing CNS. Here we show that C1q protein levels dramatically increase in the normal aging mouse and human brain, by as much as 300-fold. This increase was predominantly localized in close proximity to synapses and occurred earliest and most dramatically in certain regions of the brain, including some but not all regions known to be selectively vulnerable in neurodegenerative diseases, i.e., the hippocampus, substantia nigra, and piriform cortex. C1q-deficient mice exhibited enhanced synaptic plasticity in the adult and reorganization of the circuitry in the aging hippocampal dentate gyrus. Moreover, aged C1q-deficient mice exhibited significantly less cognitive and memory decline in certain hippocampus-dependent behavior tests compared with their wild-type littermates. Unlike in the developing CNS, the complement cascade effector C3 was only present at very low levels in the adult and aging brain. In addition, the aging-dependent effect of C1q on the hippocampal circuitry was independent of C3 and unaccompanied by detectable synapse loss, providing evidence for a novel, complement- and synapse elimination-independent role for C1q in CNS aging.
认知功能下降已成为老年健康的最大威胁之一。与年龄相关的认知能力下降是由神经元电路受到影响引起的，但负责的分子机制尚不清楚。C1q 是经典补体级联反应的起始蛋白，也是外周免疫反应的有力效应因子，它介导中枢神经系统发育过程中的突触消除。在这里，我们发现 C1q 蛋白水平在正常衰老的小鼠和人类大脑中显著增加，最高可达 300 倍。这种增加主要定位于突触附近，最早且最显著地发生在大脑的某些区域，包括但不限于在神经退行性疾病中选择性易损的某些区域，即海马体、黑质和梨状皮层。C1q 缺陷型小鼠在成年时表现出增强的突触可塑性，以及衰老海马齿状回回路的重新组织。此外，与野生型同窝仔相比，年老的 C1q 缺陷型小鼠在某些依赖海马体的行为测试中表现出明显较少的认知和记忆下降。与发育中的中枢神经系统不同，补体级联反应效应因子 C3 在成年和衰老大脑中的存在水平极低。此外，C1q 对海马体回路的衰老依赖性影响与 C3 无关，且没有伴随可检测到的突触丢失，这为 C1q 在中枢神经系统衰老中的一种新的、补体和突触消除无关的作用提供了证据。
