Sphingosylphosphorylcholine Attenuated β–Amyloid Production by Reducing BACE1 Expression and Catalysis in PC12 Cells

Abstract

Abnormal accumulation of β-amyloid (Aβ) is the main characteristic of Alzheimer's disease (AD) brain and Aβ peptides are generated from proteolytic cleavages of amyloid precursor protein (APP) by β-site APP-converting enzyme 1 (BACE1) and presenilin 1 (PS1). Sphingosylphosphorylcholine (SPC), a choline-containing sphingolipid, showed suppressive effect on Aβ production in PC12 cells which stably express Swedish mutant of amyloid precursor protein (APPsw). SPC (> 3 μM) significantly lowered the accumulation of Aβ40/42 and the expression of BACE1. However, the transcriptions of other APP processing enzymes like ADAM10 and PS1 were not affected by the SPC addition. Meanwhile, phosphocholine (PC) or other lysophospholipids, such as lysophosphatidylcholine (LPC), lysophosphatidic acid (LPA), sphingosyl-1-phosphate (S1P), did not alter BACE1 expression. Down-regulatory effect of SPC on BACE1 expression appeared to be mediated by NF-κB which is known to suppress the trans-activation of BACE1 promoter in PC12 cells. Here, the nuclear tanslocation of NF-κB was enhanced by SPC treatment in immune-fluorescent image analysis and NF-κB reporter assay. Furthermore, the catalytic activities of BACE1 and BACE2 were dose-dependently inhibited by SPC displaying IC₅₀ values of 2.79 μM and 12.05 μM, respectively. Overall, these data suggest that SPC has the potential to ameliorate Aβ pathology in neurons by down-regulating the BACE1-mediated amyloidogenic pathway.

Antimalarial Drug Artemisinin Extenuates Amyloidogenesis and Neuroinflammation in APPswe/PS1dE9 Transgenic Mice via Inhibition of Nuclear Factor‐κB and NLRP3 Inflammasome Activation

“…In the present study, artemisinin significantly inhibited the activation of NF‐κB and NALP3 inflammasome, thus leading to the decreased production of downstream cytokines (TNFα, IL‐6, IL‐1β). In fact, the antiinflammatory effects of artemisinin from NF‐κB inhibition have been proven in models of lupus nephritis, experimental autoimmune encephalomyelitis, and other disease . Our study first demonstrated the antiinflammatory effects of artemisinin in AD animal model.…”

Transcriptional and post‐transcriptional regulation of β‐secretase

“…Moreover, other different compounds lower BACE1 activity through the inhibition of NF‐κB pathway, as described recently (52, 53), suggesting that this pathway could be a useful therapeutic target.…”

Lysophospholipids and their receptors in the central nervous system

“…However, a variety of correlative signals have been observed in AD patients and relevant cellular systems. For example, two enzymes partially responsible for LPA or S1P production, autotaxin or SPHK2, respectively, have been reported to be upregulated in AD brain samples [145,146], while S1P exposure reduces the activity of the β-site APP cleaving enzyme-1 (BACE1) that causes abnormal amyloid β (Aβ) accumulation, a characteristic feature of AD [145,147]. It has also been reported that S1P levels are reduced in AD patients [148] and that Aβ downregulates another S1P synthetic enzyme, SPHK1, while overexpression of SPHK1 reduces Aβ-induced death [149].…”