Lysophosphatidic acid induces increased BACE1 expression and Aβ formation.

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.

[1]  Alfredo G. Tomasselli,et al.  Membrane-anchored aspartyl protease with Alzheimer's disease β-secretase activity , 1999, Nature.

[2]  J. Miano,et al.  Serum Response Factor-dependent Regulation of the Smooth Muscle Calponin Gene* , 2000, The Journal of Biological Chemistry.

[3]  J. Hardy,et al.  The Amyloid Hypothesis of Alzheimer ’ s Disease : Progress and Problems on the Road to Therapeutics , 2009 .

[4]  Yunzhou Dong,et al.  γ-Cleavage Is Dependent on ζ-Cleavage during the Proteolytic Processing of Amyloid Precursor Protein within Its Transmembrane Domain* , 2005, Journal of Biological Chemistry.

[5]  T. Montine,et al.  Cerebrospinal fluid lipoproteins are more vulnerable to oxidation in Alzheimer’s disease and are neurotoxic when oxidized ex vivo , 1999, Lipids.

[6]  Bryan Maloney,et al.  Functional characterization of the 5′ flanking region of the BACE gene: identification of a 91 bp fragment involved in basal level of BACE promoter expression , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[7]  Ramón Cacabelos,et al.  Cerebrovascular risk factors in Alzheimer's disease: Brain hemodynamics and pharmacogenomic implications , 2003, Neurological research.

[8]  J. Treanor,et al.  Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. , 1999, Science.

[9]  Longsheng Sun,et al.  Lysophosphatidic Acid Induces Early Growth Response Gene 1 Expression in Vascular Smooth Muscle Cells: CRE and SRE Mediate the Transcription , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[10]  P. Greengard,et al.  Cholinergic agonists and interleukin 1 regulate processing and secretion of the Alzheimer beta/A4 amyloid protein precursor. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[11]  A. Tarakhovsky,et al.  B Cell Receptor-induced cAMP-response Element-binding Protein Activation in B Lymphocytes Requires Novel Protein Kinase Cδ* , 2004, Journal of Biological Chemistry.

[12]  W. Ogawa,et al.  Thrombin Rapidly Induces Protein Kinase D Phosphorylation, and Protein Kinase C δ Mediates the Activation* , 2003, The Journal of Biological Chemistry.

[13]  H. Sorimachi,et al.  Conventional protein kinase C (PKC)‐α and novel PKCε, but not ‐δ, increase the secretion of an N‐terminal fragment of Alzheimer's disease amyloid precursor protein from PKC cDNA transfected 3Y1 fibroblasts , 1995 .

[14]  Xuemin Xu.  Gamma-secretase catalyzes sequential cleavages of the AbetaPP transmembrane domain. , 2009, Journal of Alzheimer's disease : JAD.

[15]  M. Penn,et al.  Native and Oxidized Low Density Lipoprotein Induction of Tissue Factor Gene Expression in Smooth Muscle Cells Is Mediated by Both Egr-1 and Sp1* , 1999, The Journal of Biological Chemistry.

[16]  M. Aepfelbacher,et al.  Lysophosphatidic acid mediates the rapid activation of platelets and endothelial cells by mildly oxidized low density lipoprotein and accumulates in human atherosclerotic lesions. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[17]  M. Penn,et al.  Lysophosphatidic Acid Induction of Tissue Factor Expression in Aortic Smooth Muscle Cells , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[18]  I. Kanazawa,et al.  Autotaxin expression is enhanced in frontal cortex of Alzheimer-type dementia patients , 2006, Neuroscience Letters.

[19]  P. Valet,et al.  Lysophosphatidic acid synthesis and release. , 2001, Prostaglandins & other lipid mediators.

[20]  B. Lamb,et al.  Effects of γ‐secretase cleavage‐region mutations on APP processing and Aβ formation: interpretation with sequential cleavage and α‐helical model , 2008, Journal of neurochemistry.

[21]  G. Bellomo,et al.  4-Hydroxynonenal as a biological signal: molecular basis and pathophysiological implications. , 1999, Antioxidants & redox signaling.

[22]  M. Cui.  Lysophosphatidic acid effects on atherosclerosis and thrombosis. , 2011, Clinical lipidology.

[23]  Á. Casado,et al.  Lipid Peroxidation and Antioxidant Enzyme Activities in Vascular and Alzheimer Dementias , 2008, Neurochemical Research.

[24]  P. Kehoe,et al.  Vascular risk and genetics of sporadic late-onset Alzheimer’s disease , 2004, Journal of Neural Transmission.

[25]  Hong Qing,et al.  Transcriptional Regulation of BACE1, the β-Amyloid Precursor Protein β-Secretase, by Sp1 , 2004, Molecular and Cellular Biology.

[26]  K. Blennow,et al.  Inflammatory Markers in Matched Plasma and Cerebrospinal Fluid from Patients with Alzheimer’s Disease , 2003, Dementia and Geriatric Cognitive Disorders.

[27]  R. Barbour,et al.  Purification and cloning of amyloid precursor protein β-secretase from human brain , 1999, Nature.

[28]  E. Koo,et al.  Protein Kinase C ϵ Suppresses Aβ Production and Promotes Activation of α-Secretase , 2001 .

[29]  J. Trojanowski,et al.  The relationship between oxidative/nitrative stress and pathological inclusions in Alzheimer's and Parkinson's diseases. , 2002, Free radical biology & medicine.

[30]  J. Growdon,et al.  Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. , 1992, Science.

[31]  J. Hedges,et al.  A Role for p38MAPK/HSP27 Pathway in Smooth Muscle Cell Migration* , 1999, The Journal of Biological Chemistry.

[32]  Samuel H. Wilson,et al.  Cloning and characterization of a novel member of the human ATF/CREB family: ATF2 deletion, a potential regulator of the human DNA polymerase β promoter , 2003 .

[33]  R. Wurtman,et al.  Amyloid precursor protein processing is stimulated by metabotropic glutamate receptors. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[34]  G. Perry,et al.  Oxidative Stress Increases Expression and Activity of BACE in NT2 Neurons , 2002, Neurobiology of Disease.

[35]  D. Selkoe.  Alzheimer's Disease Is a Synaptic Failure , 2002, Science.

[36]  V. Bigl,et al.  Protein kinase Cα and β1 isoforms are regulators of α‐secretory proteolytic processing of amyloid precursor protein in vivo , 2001 .

[37]  A. Levey,et al.  Multiple Effects of Aspartate Mutant Presenilin 1 on the Processing and Trafficking of Amyloid Precursor Protein* , 2001, The Journal of Biological Chemistry.

[38]  H. Cai,et al.  Mitochondrial respiratory inhibition and oxidative stress elevate β-secretase (BACE1) proteins and activity in vivo in the rat retina , 2007, Experimental Brain Research.

[39]  F. Panza,et al.  Glycerophospholipids and glycerophospholipid-derived lipid mediators: a complex meshwork in Alzheimer's disease pathology. , 2011, Progress in lipid research.

[40]  A. Takeshita,et al.  Angiotensin II Stimulates Mitogen-activated Protein Kinases and Protein Synthesis by a Ras-independent Pathway in Vascular Smooth Muscle Cells* , 1997, The Journal of Biological Chemistry.

[41]  D. Selkoe.  Alzheimer's disease: genes, proteins, and therapy. , 2001, Physiological reviews.

[42]  A. Sun,et al.  Oxidized lipoproteins may play a role in neuronal cell death in Alzheimer disease. , 1998, Molecular and chemical neuropathology.

[43]  B. Wolf,et al.  Muscarinic Regulation of Alzheimer's Disease Amyloid Precursor Protein Secretion and Amyloid β-Protein Production in Human Neuronal NT2N Cells (*) , 1995, The Journal of Biological Chemistry.

[44]  B. Wolf,et al.  Regulation of amyloid precursor protein (APP) secretion by protein kinase calpha in human ntera 2 neurons (NT2N). , 2000, Biochemistry.

[45]  Michael J. Rowan,et al.  Amyloid-β oligomers: their production, toxicity and therapeutic inhibition , 2001 .

[46]  M. Ha,et al.  Blockade of PKC epsilon activation attenuates phorbol ester-induced increase of alpha-secretase-derived secreted form of amyloid precursor protein. , 2001, Biochemical and biophysical research communications.

[47]  David G. Tew,et al.  Identification of a Novel Aspartic Protease (Asp 2) as β-Secretase , 1999, Molecular and Cellular Neuroscience.

[48]  Yunzhou Dong,et al.  Identification of a New Presenilin-dependent ζ-Cleavage Site within the Transmembrane Domain of Amyloid Precursor Protein*♦ , 2004, Journal of Biological Chemistry.