Complement Protein Isoforms in CSF as Possible Biomarkers for Neurodegenerative Disease

Abstract

It has been suggested that the activation of the complement system is involved in the pathogenesis of several neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS). Here, the CSF expression levels of complement proteins C3b, C4b, factor B, and factor H were compared between normal subjects and patients diagnosed with AD, PD, MS, and neurosyphilis. The CSF proteins were initially separated using two-dimensional gel electrophoresis, which allowed the comparison of some of the individual complement isoforms. Patients with AD, PD, and MS all showed more than one complement isoform with a significant change (p < 0.05) in CSF expression level compared to normal subjects. PD patients were found to have the greatest number of significantly changed isoforms, all showing a decreased expression level in PD CSF. The complement isoforms examined were able to distinguish between some, but not all, of the diseases studied. The data suggest that when investigating a protein as a possible biomarker, it may be useful to compare individual protein isoform expression levels in addition to the more commonly measured total protein expression level.

Cerebrospinal fluid levels of complement proteins C3, C4 and CR1 in Alzheimer’s disease

“…However, the observed differences were too small to be diagnostically useful. The findings are in line with previous reports showing that a certain isoform of C4b (Finehout et al 2005), C3 and factor H (Wang et al 2011) were elevated in CSF from AD patients.…”

Human body fluid proteome analysis

“…Discrimination of AD from controls and from other neurological diseases has been improved by simultaneous analysis of beta-amyloid (1-42), total-tau, and phosphorylated tau, where a combination of low levels of CSF-beta-amyloid 1-42 and high levels of CSF-tau and CSF-phospho-tau is associated with an AD diagnosis [335][336][337]. This may be further strengthened by the recent discovery of a number of putative CSF markers including apo A1, apo E, apo J, retinol-binding protein (RBP), kininogen, A1AT, cell cycle progression eight protein, alpha-2-HS glycoprotein (A2HSG), alpha-1 beta-glycoprotein, cathepsin B, amyloid precursor, complement proteins, glutathione independent prostaglandin D synthase [338][339][340][341][342][343]. Developing these proteins as new biomarkers may lead to the early diagnosis of AD and provide useful information in drug trials.…”

Complement regulator factor H in multiple sclerosis

“…A previous proteomic study by Finehout et al [2005] compared four complement proteins (C3, C4b, factor B (fB), and fH) on twodimensional electrophoresis gels of CSF from normal subjects (n ¼ 9) and patients diagnosed with Alzheimer's disease (n ¼ 9), Parkinson's disease (n ¼ 10), MS (n ¼ 3), and neurosyphilis (n ¼ 3). They showed a lower vol% of all four proteins in MS patients compared with normal subjects although this was only significant for one isoform of factor fB and fH.…”