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Complement C 1q‐ C 3–associated synaptic changes in multiple sclerosis hippocampus
Author(s) -
Michailidou Iliana,
Willems Janske G. P.,
Kooi EvertJan,
van Eden Corbert,
Gold Stefan M.,
Geurts Jeroen J. G.,
Baas Frank,
Huitinga Inge,
Ramaglia Valeria
Publication year - 2015
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.24398
Subject(s) - hippocampus , complement system , neuroscience , synaptophysin , multiple sclerosis , central nervous system , microglia , biology , chemistry , immunology , immunohistochemistry , antibody , inflammation
Objective Multiple 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. Methods To 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. Results C1q 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 pathway and synaptic changes. In contrast to AD, MS hippocampi were consistently negative for the terminal complement activation complex C5b9. Interpretation These data support a role for the C1q‐C3 complement axis in synaptic alterations in the MS hippocampus. Ann Neurol 2015;77:1007–1026