Complement C1q‐C3–associated synaptic changes in multiple sclerosis hippocampus

ObjectiveMultiple sclerosis (MS) is a demyelinating disease of the central nervous system, leading to memory impairment in up to 65% of patients. Memory dysfunction in MS has been associated with loss of synapses in the hippocampus, but its molecular basis is unknown. Accumulating evidence suggests that components of the complement system, C1q and C3, can mediate elimination of synapses. MethodsTo investigate the involvement of complement in synaptic changes in MS, gene and protein expression and localization of C1q and C3 were analyzed in relation to neuropathological changes in myelinated and demyelinated hippocampi from postmortem MS brains. Findings were compared to hippocampi of Alzheimer disease (AD) and non‐neurological controls. ResultsC1q expression and C3 activation were increased in myelinated and demyelinated MS hippocampi, mainly in the CA3/2 and CA1 subfields, which also showed a marked decrease in synaptic density and increased neuronal staining for the mitochondrial heat shock protein 70 (mtHSP70) stress marker. Neurons were the major source of C1q mRNA. C1q protein and activated C3 localized at synapses within human leukocyte antigen–positive cell processes and lysosomes, suggesting engulfment of complement‐tagged synapses by microglia. A significant association (p < 0.0001) between the density of C1q and synaptophysin‐positive synapses or mtHSP70 was seen in myelinated MS hippocampi, further pointing toward a link between the complement pathwa...
Source: Annals of Neurology - Category: Neurology Authors: Tags: Research Article Source Type: research