The complement cascade in Alzheimer's disease: a systematic review and meta-analysis.

Genetic evidence implicates a causal role for the complement pathway in Alzheimer's disease (AD). Since studies have shown inconsistent differences in cerebrospinal fluid (CSF) and peripheral blood complement protein concentrations between AD patients and healthy elderly, this study sought to summarize the clinical data. Original peer-reviewed articles measuring CSF and/or blood concentrations of complement or complement regulator protein concentrations in AD and healthy elderly control (HC) groups were included. Of 2966 records identified, means and standard deviations from 86 studies were summarized as standardized mean differences (SMD) by random effects meta-analyses. In CSF, concentrations of clusterin (NAD/NHC = 625/577, SMD = 0.53, Z8 = 8.81, p < 0.005; I2 < 0.005%) and complement component 3 (C3; NAD/NHC = 299/522, SMD = 0.45, Z3 = 3.21, p < 0.005; I2 = 68.40%) were significantly higher in AD, but differences in C1q, C-reactive protein (CRP), serum amyloid protein (SAP), and factor H concentrations were not significant. In peripheral blood, concentrations of CRP were elevated in AD (NAD/NHC = 3404/3332, SMD = 0.44, Z43 = 3.43, p < 0.005; I2 = 93.81%), but differences between groups in C3, C4, C1-inhibitor, SAP, factor H and clusterin concentrations were not significant, and inconsistent between studies. Of 64 complement pathway proteins or regulators in the quantitative synthesis, trends in C1q, factor B, C4a, and late-stage complement pathway components (e.g. C9) in blood, C4 in CSF, and the membrane attack complex in blood and CSF, might be investigated further. The results collectively support elevated complement pathway activity in AD, which was best characterized by increased CSF clusterin concentrations and less consistently by CSF C3 concentrations. Complement activity related to an AD diagnosis was not reflected consistently by the peripheral blood proteins investigated.

Author Correction: Towards an arthritis flare-responsive drug delivery system.

In the original version of this Article, financial support was not fully acknowledged. The PDF and HTML versions of the Article have now been corrected to include support from the National Football League Players Association.

Towards an arthritis flare-responsive drug delivery system.

Local delivery of therapeutics for the treatment of inflammatory arthritis (IA) is limited by short intra-articular half-lives. Since IA severity often fluctuates over time, a local drug delivery method that titrates drug release to arthritis activity would represent an attractive paradigm in IA therapy. Here we report the development of a hydrogel platform that exhibits disassembly and drug release controlled by the concentration of enzymes expressed during arthritis flares. In vitro, hydrogel loaded with triamcinolone acetonide (TA) releases drug on-demand upon exposure to enzymes or synovial fluid from patients with rheumatoid arthritis. In arthritic mice, hydrogel loaded with a fluorescent dye demonstrates flare-dependent disassembly measured as loss of fluorescence. Moreover, a single dose of TA-loaded hydrogel but not the equivalent dose of locally injected free TA reduces arthritis activity in the injected paw. Together, our data suggest flare-responsive hydrogel as a promising next-generation drug delivery approach for the treatment of IA.