title: 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.
authors.affiliation: Department of Biomedical and Diagnostic Sciences, University of Tennessee, Knoxville, TN 37996, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Shi
authors.forename: Yunzhou
authors.initials: Y
authors.lastname: Dong
authors.forename: Mei-Zhen
authors.initials: MZ
authors.lastname: Cui
authors.forename: Xuemin
authors.initials: X
authors.lastname: Xu
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D015854:Up-Regulation
chemical_list: D016229:Amyloid beta-Peptides; D008077:Lipoproteins, LDL; D008246:Lysophospholipids; C099252:oxidized low density lipoprotein; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C032881:lysophosphatidic acid