Complement Component C3 and Butyrylcholinesterase Activity Are Associated with Neurodegeneration and Clinical Disability in Multiple Sclerosis

Abstract

Dysregulation of the complement system is evident in many CNS diseases but mechanisms regulating complement activation in the CNS remain unclear. In a recent large rat genome-wide expression profiling and linkage analysis we found co-regulation of complement C3 immediately downstream of butyrylcholinesterase (BuChE), an enzyme hydrolyzing acetylcholine (ACh), a classical neurotransmitter with immunoregulatory effects. We here determined levels of neurofilament-light (NFL), a marker for ongoing nerve injury, C3 and activity of the two main ACh hydrolyzing enzymes, acetylcholinesterase (AChE) and BuChE, in cerebrospinal fluid (CSF) from patients with MS (n = 48) and non-inflammatory controls (n = 18). C3 levels were elevated in MS patients compared to controls and correlated both to disability and NFL. C3 levels were not induced by relapses, but were increased in patients with ≥9 cerebral lesions on magnetic resonance imaging and in patients with progressive disease. BuChE activity did not differ at the group level, but was correlated to both C3 and NFL levels in individual samples. In conclusion, we show that CSF C3 correlates both to a marker for ongoing nerve injury and degree of disease disability. Moreover, our results also suggest a potential link between intrathecal cholinergic activity and complement activation. These results motivate further efforts directed at elucidating the regulation and effector functions of the complement system in MS, and its relation to cholinergic tone.

Targeted complement inhibition at synapses prevents microglial synaptic engulfment and synapse loss in demyelinating disease

“…Similarly, clinical studies have shown increased plasma levels of C3 and elevated C3 in the CSF of MS patients, which correlate with disease severity and clinical disability (Ingram et al, 2012, Ingram et al, 2014, Tatomir et al, 2017). Interestingly, patients with progressive MS, particularly those with primary progressive MS, showed the highest concentrations of C3 in the CSF and plasma (Ingram et al, 2012, Aeinehband et al, 2015).…”

“…Interestingly, this classical complement cascade-mediated phagocytic signaling has now been identified to be aberrantly upregulated in mouse models of Alzheimer’s disease, frontotemporal dementia, and West Nile Virus infection, leading to synapse loss (Hong et al, 2016, Vasek et al, 2016, Lui et al, 2016). In MS patients, complement proteins are elevated systemically and in the CNS (Aeinehband et al, 2015, Ingram et al, 2012, Ingram et al, 2009, Watkins et al, 2016), and recent work has suggested that C1q and C3 colocalize with synaptic proteins in postmortem MS brains (Michailidou et al, 2015). However, it remains elusive if complement and/or microglia are necessary for synaptic changes in MS.…”

Cerebrospinal fluid complement system biomarkers in demyelinating disease

“…5 These AQP4-Ab negative NMOSD patients can present with symptoms also encountered in MS and CIS, and correct diagnosis remains challenging. We and others have shown that complement activation drives pathology in both NMOSD and MS [6][7][8][9][10][11][12][13][14][15][16][17] , with evidence from immunohistochemistry 6,[13][14]16,18,23 as well as studies measuring complement proteins in cerebrospinal fluid (CSF) and plasma/serum 7,8,[10][11][12]17,19,20 . In our previous study of plasma complement biomarkers 20 we found that several complement proteins and activation products were higher in NMOSD compared to MS or controls and a model comprising C1 inhibitor…”

The complement system as a biomarker of disease activity and response to treatment in multiple sclerosis

“…The highest levels were seen in progressive MS patients, especially those with primary progressive MS (PPMS) (Table 2); in contrast, the NFL CSF levels were higher in RRMS patients. There was no difference in the C3 CSF levels between relapsing patients and patients in remission [22]. …”