S4-02-03: complement in alzheimer's disease: lessons from c3-deficient mice

The complement system is an innate immune response to remove pathogens and cellular debris, and has also been reported recently to be involved in neurogenesis and microglia-mediated synaptic pruning during brain development. Complement C3, central to multiple complement pathways, is elevated in Alzheimer's disease (AD) and appears to contribute to Abeta clearance by microglia. Recently, we demonstrated age-dependent synapse and neuron loss in CA3 of hippocampus in aged C56BL/6 WT mice but not in aged C3-deficient mice. C3 KO mice were less anxious and had better memory than their WT counterparts. Thus, we asked whether C3 plays a role in AD in APP/PS1dE9 Tg mice. Male C3-deficient (C3KO), C57BL/6 WT, APP/PS1dE9 and APP/PS1;C3KO mice (∼20/group) were aged to P30, 4 mo and 16 mo of age. Behavioral testing was performed just prior to sacrifice in the oldest mice. Pathological and biochemical analyses were performed on mouse brain tissues. C3KO mice had similar locomotion as WT mice but showed enhanced cognition in several tests. APP/PS1 Tg mice demonstrated increased locomotor activity in the Open Field and deficits in the Water T Maze and Contextual Fear Conditioning (trend) compared to WT mice. C3-deficiency in APP/PS1 Tg mice normalized locomotor activity and spatial memory to that of WT mice. C3 KO and APP/PS1;C3KO mice showed an anxiolytic phenotype in the Elevated Plus Maze. Abeta burden was similar between APP/PS1 and APP/PS1;C3KO mice at 4 mo but elevated in the cortex and hippocampus of 16 mo-old APP/PS1;C3KO mice. No differences in neurons or glia were observed at P30 or 4 mo of age but there were more CA3 neurons in 16 mo-old APP/PS1;C3KO mice. C3-deficiency reduced microglial priming and astrocyte clustering at plaques in 16 mo-old APP/PS1 mice without altering glial number. At 16 mo, mature BDNF and its receptor, TrkB, were elevated in C3KOs and reduced in APP/PS1 mice compared to WT mice, and normalized to WT levels in C3-deficient APP/PS1 mice. Lifelong C3-deficiency in mice protects against age-related cognitive decline, even in the context of enhanced Abeta plaque deposition, possibly by modulating microglial function and protecting synapses.