Complement C1q-C3-associated synaptic changes in multiple sclerosis hippocampus
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Complement C1q-C3-associated synaptic changes in multiple sclerosis hippocampus. / Michailidou, Iliana; Willems, Janske G P; Kooi, Evert-Jan; van Eden, Corbert; Gold, Stefan M; Geurts, Jeroen J G; Baas, Frank; Huitinga, Inge; Ramaglia, Valeria.
In: ANN NEUROL, Vol. 77, No. 6, 06.2015, p. 1007-26.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 -