Downregulation of protein phosphatase 2A by apolipoprotein E: Implications for Alzheimer's disease

被引:36
作者
Theendakara, Veena [1 ]
Bredesen, Dale E. [1 ,2 ]
Rao, Rammohan V. [1 ]
机构
[1] Buck Inst Res Aging, 8001 Redwood Blvd, Novato, CA 94945 USA
[2] UCLA, Easton Ctr Alzheimers Dis Res, Los Angeles, CA 90025 USA
关键词
Alzheimer's disease; PP2A; PPP2R5E; PP2A(C); PME-1; PHF; Tau; TAU-PHOSPHORYLATION; AMYLOID HYPOTHESIS; IPSC LINES; PP2A; SUBUNITS; METHYLATION; HOMOCYSTEINE; INFLAMMATION; TARGET; BETA;
D O I
10.1016/j.mcn.2017.07.002
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The apolipoprotein E epsilon 4 allele is the single most important genetic risk factor associated with Alzheimer's disease (AD). Tau phosphorylation and hyperphosphorylation is an underlying feature of AD and is regulated by specific kinases and phosphatases. Among phosphatases, protein phosphatase 2A (PP2A) is the principal tau dephos-phorylating enzyme in the brain. Several abnormalities of PP2A have been reported in AD, including among others decreased protein levels of PP2A, decreased mRNA and protein levels of the catalytic subunit PP2A(C) and variable regulatory B subunits and reduced methylation of the catalytic subunit, all of which results in disruption of the PP2A phosphatase activity. In earlier studies we described a novel mechanism for ApoE as a transcription factor that binds regions of double-stranded DNA with high affinity, including the promoter regions of similar to 3000 different genes. The list of genes also included PPP2R5E (B56 epsilon), a regulatory B' subunit of protein phosphatase 2A. Using a combination of A172 human glioblastoma cells, ApoE(3/4) and ApoE(-/-) NSC and human postmortem tissue, we now demonstrate that ApoE not only binds to the PPP2R5E promoter but also triggers a significant reduction in PP2A activity by two mechanisms: 1) ApoE transcriptionally represses PPP2R5E and reduces protein expression, and 2) ApoE triggers demethylation of the catalytic subunit (PP2A(C)) of PP2A, resulting in the disruption of the PPP2R5E-PP2A(C) complex. Our results indicated a significant down-regulation of PPP2R5E gene expression and reduction in PP2A activity by ApoE4 compared with ApoE3. This may also explain an elevated Tau phosphorylation in AD human brains that featured at least one ApoE4 allele. Thus, our present work links ApoE and PPP2R5E expression to a reduction in the PP2A catalytic activity that has implications for Alzheimer's disease. (C) 2017 Elsevier Inc. All rights reserved.
引用
收藏
页码:83 / 91
页数:9
相关论文
共 48 条
[1]   Protein Phosphatases and Alzheimer's Disease [J].
Braithwaite, Steven P. ;
Stock, Jeffry B. ;
Lombroso, Paul J. ;
Nairn, Angus C. .
PROTEIN PHOSPHORYLATION IN HEALTH AND DISEASE, 2012, 106 :343-379
[2]   Metabolic profiling distinguishes three subtypes of Alzheimer's disease [J].
Bredesen, Dale E. .
AGING-US, 2015, 7 (08) :595-600
[3]   Low frequency of alterations of the α (PPP2R1A) and β (PPP2R1B) isoforms of the subunit A of the serine-threonine phosphatase 2A in human neoplasms [J].
Calin, GA ;
di Iasio, MG ;
Caprini, E ;
Vorechovsky, I ;
Natali, PG ;
Sozzi, G ;
Croce, CM ;
Barbanti-Brodano, G ;
Russo, G ;
Negrini, M .
ONCOGENE, 2000, 19 (09) :1191-1195
[4]   Apolipoprotein E and Peptide Mimetics Modulate Inflammation by Binding the SET Protein and Activating Protein Phosphatase 2A [J].
Christensen, Dale J. ;
Ohkubo, Nobutaka ;
Oddo, Jessica ;
Van Kanegan, Michael J. ;
Neil, Jessica ;
Li, Fengqiao ;
Colton, Carol A. ;
Vitek, Michael P. .
JOURNAL OF IMMUNOLOGY, 2011, 186 (04) :2535-2542
[5]   Protein phosphatase 2A regulatory subunits and cancer [J].
Eichhorn, Pieter J. A. ;
Creyghton, Menno P. ;
Bernards, Rene .
BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER, 2009, 1795 (01) :1-15
[6]   Systemic inflammation, infection, apoE alleles, and Alzheimer disease: A position paper [J].
Finch, Caleb E. ;
Morgan, Todd E. .
CURRENT ALZHEIMER RESEARCH, 2007, 4 (02) :185-189
[7]   Evolution of the human lifespan and diseases of aging: Roles of infection, inflammation, and nutrition [J].
Finch, Caleb E. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 :1718-1724
[8]   The role of tau in neurodegeneration [J].
Gendron, Tania F. ;
Petrucelli, Leonard .
MOLECULAR NEURODEGENERATION, 2009, 4
[9]   Medicine - The amyloid hypothesis of Alzheimer's disease: Progress and problems on the road to therapeutics [J].
Hardy, J ;
Selkoe, DJ .
SCIENCE, 2002, 297 (5580) :353-356
[10]   Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins [J].
Huynh, Tien-Phat V. ;
Davis, Albert A. ;
Ulrich, Jason D. ;
Holtzman, David M. .
JOURNAL OF LIPID RESEARCH, 2017, 58 (05) :824-836