Complement 3 and Factor H in Human Cerebrospinal Fluid in Parkinson's Disease, Alzheimer's Disease, and Multiple-System Atrophy

Abstract

Complement activation, a key component of neuroinflammation, has been reported in both Parkinson's disease (PD) and Alzheimer's disease (AD). However, it is unclear whether complement activation and neuroinflammation in general are distinctly different from each another in major neurodegenerative disorders. In the present study, cerebrospinal fluid complement 3 (C3) and factor H (FH) were measured and evaluated together with amyloid-β(42) (Aβ(42)), which in recent investigations was decreased in patients with PD, in particular those with cognitive impairment. The study included 345 participants: 126 patients with PD at various stages with or without cognitive impairment, 50 with AD, and 32 with multiple-system atrophy, and 137 healthy control individuals. In addition to changes in Aβ(42) concentrations, there were clear differences in the patterns of complement profiles among neurodegenerative disorders. The C3/FH ratio demonstrated high sensitivity and specificity in differentiating patients with multiple-system atrophy from those with AD or PD and control individuals. In addition, the C3/Aβ(42) and FH/Aβ(42) ratios not only correlated with PD severity approximated using the Unified Parkinson's Disease Rating Scale but also with the presence of cognitive impairment or dementia in PD. Both C3 and FH correlated with the severity of impairment in AD as indicated using Mini-Mental State Examination scores.

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.…”

Astrocyte-Microglia Cross Talk through Complement Activation Modulates Amyloid Pathology in Mouse Models of Alzheimer's Disease

“…In the CNS, complement factors C3 and C1q serve not only as mediators of innate immunity, but also coordinate microglial engulfment of supernumerary spines to ensure synaptic refinement and neuronal survival during circuit development (Stevens et al, 2007;Shinjyo et al, 2009;Benoit and Tenner, 2011). In disease, the complement system is strongly activated by neuronal damage, consistent with the observation of prominent complement protein expression in response to A␤ exposure and in AD brain tissue (Bradt et al, 1998;Tacnet-Delorme et al, 2001;Fan and Tenner, 2004;Loeffler et al, 2008;Wang et al, 2011). The identification of complement receptor 1 as a genetic risk factor in AD (Lambert et al, 2009;Crehan et al, 2012) raises the possibility that complement activation may be an active participant in AD pathogenesis rather than a passive consequence of amyloid deposition.…”

Cerebrospinal Fluid Peptides as Potential Parkinson Disease Biomarkers: A Staged Pipeline for Discovery and Validation*

“…those from DJ-1), even though they were included in the list, failed to pass our rigorous pipeline selection criteria. That said, a peptide from complement factor C3 (C3), a potential marker identified in CSF in our previous study (58), did appear as one of the 17 peptides identified in the training set. In further investigations, we will try to optimize the conditions to include not only these robust biomarker candidates but also known potential markers such as ␣-synuclein and DJ-1 for an "ideal" panel of markers to be used clinically.…”