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


CONCLUSIONS
These data support a role for the C1q-C3 complement axis in synaptic alterations in the MS hippocampus.
Department of Genome Analysis, Academic Medical Center, Amsterdam, the Netherlands.
Iliana
I
Michailidou
Department of Genome Analysis, Academic Medical Center, Amsterdam, the Netherlands.|Department of Neuroimmunology, Netherlands Institute for Neuroscience, Amsterdam, the Netherlands.
Janske G P
JG
Willems
Department of Anatomy and Neurosciences, VU University Medical Center, Amsterdam, the Netherlands.
Evert-Jan
EJ
Kooi
Department of Neuroimmunology, Netherlands Institute for Neuroscience, Amsterdam, the Netherlands.
Corbert
C
van Eden
Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|Department of Psychiatry, Charité, Berlin, Germany.
Stefan M
SM
Gold
Department of Anatomy and Neurosciences, VU University Medical Center, Amsterdam, the Netherlands.
Jeroen J G
JJ
Geurts
Department of Genome Analysis, Academic Medical Center, Amsterdam, the Netherlands.
Frank
F
Baas
Department of Neuroimmunology, Netherlands Institute for Neuroscience, Amsterdam, the Netherlands.
Inge
I
Huitinga
Department of Genome Analysis, Academic Medical Center, Amsterdam, the Netherlands.|Department of Neuroimmunology, Netherlands Institute for Neuroscience, Amsterdam, the Netherlands.
Valeria
V
Ramaglia
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D015922:Complement C1q / Q000378:metabolism*; D003176:Complement C3 / Q000378:metabolism*; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000473:pathology*; D014015:Tissue Banks
D003176:Complement C3; D012333:RNA, Messenger; D015922:Complement C1q