A Dramatic Increase of C1q Protein in the CNS during Normal Aging

Abstract

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.

Cortical plasticity induced by transplantation of embryonic somatostatin or parvalbumin interneurons

“…Signals that are part of the immune response can affect plasticity in the visual pathway (25,26), including ODP (27,28). Although cell death in our depletion experiments might stimulate an immune response, our PV-SST-depleted transplants, which presumably had an immune response similar to or greater than that of PV-depleted or SST-depleted transplants, did not induce plasticity.…”

Microglial dysfunction as a key pathological change in adrenomyeloneuropathy

“…Colocalization of C1q and synaptophysin in Abcd1 –/– mice of different ages suggests that microglia mediate synaptic pruning. During postnatal development and in the normal aging process, the complement pathway plays a critical role in the refinement of neural circuits 10, 33, 34, 35, 36. In AMN, abnormal synaptic pruning attributed to excessive microglial activation may instead promote neurodegeneration, as also observed in many neurodegenerative disease models 10, 36…”

Neutrophils Induce Astroglial Differentiation and Migration of Human Neural Stem Cells via C1q and C3a Synthesis

“…However, C1q can be synthesized in the absence of C1r and C1s by a variety of cell types, including PMN (47,70,71). Furthermore, a large body of evidence has shown upregulation of C1q in the CNS following injury/disease/aging (72)(73)(74), suggesting that C1q alone may have nontraditional functions (75,76). In contrast, all known functions of C3 are mediated by its cleavage products, C3b and C3a.…”