Promotion of β-amyloid production by C-reactive protein and its implications in the early pathogenesis of Alzheimer's disease.
C-reactive protein (CRP) and β-amyloid protein (Aβ) are involved in the development of Alzheimer's disease (AD). However, the relationship between CRP and Aβ production is unclear. In vitro and in vivo experiments were performed to investigate the association of CRP with Aβ 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. Aβ1-42 was measured by enzyme-linked immunosorbent assay. The relevance of CRP and Aβ 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 Aβ1-42 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 Aβ1-42, but did not reversed Aβ1-42 cytotoxicity. The cerebral levels of CRP and Aβ1-42 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 Aβ formation and Aβ-related markers expressions; CRP and Aβ were relevant in early-stage AD; CRP may be an important trigger in AD pathogenesis.
Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.
Bing-Tian
BT
Bi
Huan-Bing
HB
Lin
Yu-Fang
YF
Cheng
Heng
H
Zhou
Ting
T
Lin
Ming-Zi
MZ
Zhang
Tie-Jun
TJ
Li
Jiang-Ping
JP
Xu
D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors; D015153:Blotting, Western; D002097:C-Reactive Protein / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004396:Coloring Agents; D003172:Complement C1 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016716:PC12 Cells; D053764:Presenilin-1 / Q000096:biosynthesis; D053766:Presenilin-2 / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D013778:Tetrazolium Salts; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016229:Amyloid beta-Peptides; D004396:Coloring Agents; D003172:Complement C1; D053764:Presenilin-1; D053766:Presenilin-2; D012333:RNA, Messenger; D013778:Tetrazolium Salts; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein; D007770:L-Lactate Dehydrogenase; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509281:Bace1 protein, rat; C022616:thiazolyl blue