Lysophosphatidic acid induces increased BACE1 expression and Aβ formation

Abstract

The abnormal production and accumulation of β-amyloid peptide (Aβ), which is produced from amyloid precursor protein (APP) by the sequential actions of β-secretase and γ-secretase, are thought to be the initial causative events in the development of Alzheimer’s disease (AD). Accumulating evidence suggests that vascular factors play an important role in the pathogenesis of AD. Specifically, studies have suggested that one vascular factor in particular, oxidized low density lipoprotein (oxLDL), may play an important role in regulating Aβ formation in AD. However, the mechanism by which oxLDL modulates Aβ formation remains elusive. In this study, we report several new findings that provide biochemical evidence suggesting that the cardiovascular risk factor oxLDL may contribute to Alzheimer’s disease by increasing Aβ production. First, we found that lysophosphatidic acid (LPA), the most bioactive component of oxLDL induces increased production of Aβ. Second, our data strongly indicate that LPA induces increased Aβ production via upregulating β-secretase expression. Third, our data strongly support the notion that different isoforms of protein kinase C (PKC) may play different roles in regulating APP processing. Specifically, most PKC members, such as PKCα, PKCβ, and PKCε, are implicated in regulating α-secretase-mediated APP processing; however, PKCδ, a member of the novel PKC subfamily, is involved in LPA-induced upregulation of β-secretase expression and Aβ production. These findings may contribute to a better understanding of the mechanisms by which the cardiovascular risk factor oxLDL is involved in Alzheimer’s disease.

Lysophosphatidic Acid Signaling in the Nervous System

“…LPA enhances site-specific pathogenic tau phosphorylation, leading to GSK3-mediated growth cone collapse in neurons (Sayas et al, 1999). LPA also increases β-secretase activity, leading to elevated Aβ production (Shi et al, 2013). Gintonin, a bioactive fraction isolated from ginseng that has been reported to improve cognition in AD, is composed of protein-bound LPA that can activate LPA 1-5 .…”

TNF-α regulates the proteolytic degradation of ST6Gal-1 and endothelial cell-cell junctions through upregulating expression of BACE1

“…A recent study has demonstrated the existence of a positive correlation between PKC signaling cascade activation and increased BACE1 expression in fibroblasts and neuroblastoma cells, thus suggesting that PKC signaling cascades may be involved in BACE1 expression in vascular endothelial cells2627. To gain insight into the potential signaling pathways regulating BACE1 expression and protein sialylation levels, phospho-PKC δ and PKC δ protein levels were determined via western blotting analysis.…”

“…Many studies have confirmed that PKC signaling is involved in BACE1 upregulation in neuroblastoma and fibroblast cell lines2627. It is well known that PKC activation is induced by TNFR members, such as TNFR1, FAS (TNFRSF6), OX40, and TRAIL-R1/240.…”

Blood‐based metabolic signatures in Alzheimer's disease

“…Previously, oxidized lipoproteins have been identified as a possible oxidative stressor in the brain leading to neuronal cell death in AD [42]. LPA is the most bioactive fraction of oxidized low-density lipoprotein [43]. It has an important signal function and has been linked to the pathogenesis of AD as in vitro results suggest they support tau phosphorylation and raise levels of β-secretase, leading to increased Aβ production [43], [44], [45].…”

“…LPA is the most bioactive fraction of oxidized low-density lipoprotein [43]. It has an important signal function and has been linked to the pathogenesis of AD as in vitro results suggest they support tau phosphorylation and raise levels of β-secretase, leading to increased Aβ production [43], [44], [45]. Moreover, LPAs have been identified as important factors in vascular development, atherosclerosis, and atherotrombogenesis [46], [47], [48].…”