Complement C3-Deficient Mice Fail to Display Age-Related Hippocampal Decline.

The complement system is part of the innate immune response responsible for removing pathogens and cellular debris, in addition to helping to refine CNS neuronal connections via microglia-mediated pruning of inappropriate synapses during brain development. However, less is known about the role of complement during normal aging. Here, we studied the role of the central complement component, C3, in synaptic health and aging. We examined behavior as well as electrophysiological, synaptic, and neuronal changes in the brains of C3-deficient male mice (C3 KO) compared with age-, strain-, and gender-matched C57BL/6J (wild-type, WT) control mice at postnatal day 30, 4 months, and 16 months of age. We found the following: (1) region-specific and age-dependent synapse loss in aged WT mice that was not observed in C3 KO mice; (2) age-dependent neuron loss in hippocampal CA3 (but not in CA1) that followed synapse loss in aged WT mice, neither of which were observed in aged C3 KO mice; and (3) significantly enhanced LTP and cognition and less anxiety in aged C3 KO mice compared with aged WT mice. Importantly, CA3 synaptic puncta were similar between WT and C3 KO mice at P30. Together, our results suggest a novel and prominent role for complement protein C3 in mediating aged-related and region-specific changes in synaptic function and plasticity in the aging brain. Significance statement: The complement cascade, part of the innate immune response to remove pathogens, also plays a role in synaptic refinement during brain development by the removal of weak synapses. We investigated whether complement C3, a central component, affects synapse loss during aging. Wild-type (WT) and C3 knock-out (C3 KO) mice were examined at different ages. The mice were similar at 1 month of age. However, with aging, WT mice lost synapses in specific brain regions, especially in hippocampus, an area important for memory, whereas C3 KO mice were protected. Aged C3 KO mice also performed better on learning and memory tests than aged WT mice. Our results suggest that complement C3, or its downstream signaling, is detrimental to synapses during aging.

Dysregulation of FMRP/mTOR Signaling Cascade in Hypoxic-Ischemic Injury of Premature Human Brain.

In this study the authors investigated whether dysregulation of the fragile X mental retardation protein and mammalian target of rapamycin signaling cascade can have a role in the pathogenesis of encephalopathy of prematurity following perinatal hypoxia-ischemia. The authors examined the brain tissue of newborns with encephalopathy and compared it to age-matched controls with normal brain development and adults. In normal controls, the fragile X mental retardation protein expression in cortical gray matter spiked 4-fold during 36-39 gestational weeks compared to the adult, with a concomitant suppression of p70S6K and S6. In encephalopathy cases, the developmental spike of fragile X mental retardation protein was not observed, and fragile X mental retardation protein levels remained significantly lower than in normal controls. Importantly, this fragile X mental retardation protein downregulation was followed by a significant overexpression of p70S6K and S6. These novel findings thus suggest that premature hypoxic-ischemic brain injury can affect the fragile X mental retardation protein/mammalian target of rapamycin pathway, as otherwise observed in inherited syndromes of cognitive disability and autism spectrum disorders.

Complement and microglia mediate early synapse loss in Alzheimer mouse models.

Synapse loss in Alzheimer's disease (AD) correlates with cognitive decline. Involvement of microglia and complement in AD has been attributed to neuroinflammation, prominent late in disease. Here we show in mouse models that complement and microglia mediate synaptic loss early in AD. C1q, the initiating protein of the classical complement cascade, is increased and associated with synapses before overt plaque deposition. Inhibition of C1q, C3, or the microglial complement receptor CR3 reduces the number of phagocytic microglia, as well as the extent of early synapse loss. C1q is necessary for the toxic effects of soluble ß-amyloid (Aß) oligomers on synapses and hippocampal long-term potentiation. Finally, microglia in adult brains engulf synaptic material in a CR3-dependent process when exposed to soluble Aß oligomers. Together, these findings suggest that the complement-dependent pathway and microglia that prune excess synapses in development are inappropriately activated and mediate synapse loss in AD.