Lysophosphatidic acid induces increased BACE1 expression and A beta formation

作者：Shi Jing; Dong Yunzhou; Cui Mei Zhen^*; Xu Xuemin

来源：Biochimica et Biophysica Acta-Molecular Basis of Disease, 2013, 1832(1): 29-38.

DOI：10.1016/j.bbadis.2012.09.010

• Alzheimer's disease
• Lysophosphatidic acid
• Oxidized LDL
• beta-Secretase
• Beta-amyloid peptide
• Amyloid precursor protein

The abnormal production and accumulation of beta-amyloid peptide (A beta), which is produced from amyloid precursor protein (APP) by the sequential actions of beta-secretase and gamma-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 A beta formation in AD. However, the mechanism by which oxLDL modulates A beta 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 A beta production. First, we found that lysophosphatidic acid (LPA), the most bioactive component of oxLDL induces increased production of A beta. Second, our data strongly indicate that LPA induces increased A beta production via upregulating beta-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 PKC alpha, PKc beta, and PKC epsilon, are implicated in regulating alpha-secretase-mediated APP processing; however, PKC delta, a member of the novel PKC subfamily, is involved in LPA-induced upregulation of beta-secretase expression and A beta 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.

• 出版日期2013-1