Apolipoprotein E modulates gamma-secretase cleavage of the amyloid precursor protein.
Polymorphisms in the apolipoprotein E (APOE) gene affect the risk of Alzheimer disease and the amount of amyloid beta-protein (Abeta) deposited in the brain. The apoE protein reduces Abeta levels in conditioned media from cells in culture, possibly through Abeta clearance mechanisms. To explore this effect, we treated multiple neural and non-neural cell lines for 24 h with apoE at concentrations similar to those found in the cerebrospinal fluid (1-5 microg/mL). The apoE treatment reduced Abeta40 by 60-80% and Abeta42 to a lesser extent (20-30%) in the conditioned media. Surprisingly, apoE treatment resulted in an accumulation of amyloid precursor protein (APP)-C-terminal fragments in cell extracts and a marked reduction of APP intracellular domain-mediated signaling, consistent with diminished gamma-secretase processing of APP. All three isoforms of apoE, E2, E3 and E4, had similar effects on Abeta and APP-C-terminal fragments, and the effects were independent of the low-density lipoprotein receptor family. Apolipoprotein E had minimal effects on Notch cleavage and signaling in cell-based assays. These data suggest that apoE reduces gamma-secretase cleavage of APP, lowering secreted Abeta levels, with stronger effects on Abeta40. The apoE modulation of Abeta production and APP signaling is a potential mechanism affecting Alzheimer disease risk.
Alzheimer Disease Research Unit, Massachusetts General Hospital-East, Charlestown, Massachusetts, USA.
Michael C
MC
Irizarry
Amy
A
Deng
Alberto
A
Lleo
Oksana
O
Berezovska
Christine A F
CA
Von Arnim
Matthew
M
Martin-Rehrmann
Arlene
A
Manelli
Mary Jo
MJ
LaDu
Bradley T
BT
Hyman
G William
GW
Rebeck
D048868:Adaptor Proteins, Signal Transducing; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases; D015153:Blotting, Western / Q000379:methods; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D007668:Kidney; D026563:LDL-Receptor Related Protein-Associated Protein / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000494:pharmacology; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D009447:Neuroblastoma; D010446:Peptide Fragments / Q000378:metabolism; D051381:Rats; D051880:Receptors, Notch; D013997:Time Factors; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection / Q000379:methods; D014280:Triglycerides / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology
C466684:APBB2 protein, human; D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D002352:Carrier Proteins; D026563:LDL-Receptor Related Protein-Associated Protein; D008075:Lipoproteins, HDL; D008565:Membrane Proteins; D010446:Peptide Fragments; D051880:Receptors, Notch; D014280:Triglycerides; D005680:gamma-Aminobutyric Acid; C057077:1,2-dilinolenoyl-3-(4-aminobutyryl)propane-1,2,3-triol; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse