Promotion of ß-amyloid production by C-reactive protein and its implications in the early pathogenesis of Alzheimer's disease.

ABSTRACT

C-reactive protein (CRP) and ß-amyloid protein (Aß) are involved in the development of Alzheimer's disease (AD). However, the relationship between CRP and Aß production is unclear. In vitro and in vivo experiments were performed to investigate the association of CRP with Aß production. Using the rat adrenal pheochromocytoma cell line (PC12 cells) to mimic neurons, cytotoxicity was evaluated by cell viability and supernatant lactate dehydrogenase (LDH) activity. The levels of amyloid precursor protein (APP), beta-site APP cleaving enzyme (BACE-1), and presenilins (PS-1 and PS-2) were investigated using real-time polymerase chain reaction and Western blotting analysis. Aß1-42 was measured by enzyme-linked immunosorbent assay. The relevance of CRP and Aß as well as potential mechanisms were studied using APP/PS1 transgenic (Tg) mice. Treatment with 0.5-4.0 µM CRP for 48 h decreased cell viability and increased LDH leakage in PC12 cells. Incubation with CRP at a sub-toxic concentration of 0.2 µM increased the mRNA levels of APP, BACE-1, PS-1, and PS-2, as well as Aß1-42 production. CRP inhibitor reversed the CRP-induced upregulations of the mRNA levels of APP, BACE-1, PS-1, and PS-2, and the protein levels of APP, BACE-1, PS-1, and Aß1-42, but did not reversed Aß1-42 cytotoxicity. The cerebral levels of CRP and Aß1-42 in APP/PS1 Tg mice were positively correlated, accompanied with the elevated mRNA expressions of serum amyloid P component (SAP), complement component 1q (C1q), and tumor necrosis factor-α (TNF-α). These results suggest that CRP cytotoxicity is associated with Aß formation and Aß-related markers expressions; CRP and Aß were relevant in early-stage AD; CRP may be an important trigger in AD pathogenesis.