Complement C1q-C3-associated synaptic changes in multiple sclerosis hippocampus

TY - JOUR

T1 - Complement C1q-C3-associated synaptic changes in multiple sclerosis hippocampus

AU - Michailidou, Iliana

AU - Willems, Janske G P

AU - Kooi, Evert-Jan

AU - van Eden, Corbert

AU - Gold, Stefan M

AU - Geurts, Jeroen J G

AU - Baas, Frank

AU - Huitinga, Inge

AU - Ramaglia, Valeria

N1 - © 2015 American Neurological Association.

PY - 2015/6

Y1 - 2015/6

N2 - 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.

AB - 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.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Alzheimer Disease

KW - Cell Count

KW - Complement C1q

KW - Complement C3

KW - Female

KW - Hippocampus

KW - Humans

KW - Male

KW - Middle Aged

KW - Multiple Sclerosis

KW - RNA, Messenger

KW - Synapses

KW - Tissue Banks

U2 - 10.1002/ana.24398

DO - 10.1002/ana.24398

M3 - SCORING: Journal article

C2 - 25727254

VL - 77

SP - 1007

EP - 1026

JO - ANN NEUROL

JF - ANN NEUROL

SN - 0364-5134

IS - 6

ER -