ApoE mimetic peptide decreases Abeta production in vitro and in vivo.
BACKGROUND
Apolipoprotein E (apoE) is postulated to affect brain Abeta levels through multiple mechanisms--by altering amyloid precursor protein (APP) processing, Abeta degradation, and Abeta clearance. We previously showed that an apoE-derived peptide containing a double repeat of the receptor-binding region was similarly effective in increasing APP processing in vivo. Here, we further examined whether peptides containing tandem repeats of the apoE receptor-binding region (amino acids 141-149) affected APP trafficking, APP processing, and Abeta production.


RESULTS
We found that peptides containing a double or triple tandem repeat of the apoE receptor-binding region, LRKLRKRLL, increased cell surface APP and decreased Abeta levels in PS1-overexpressing PS70 cells and in primary neurons. This effect was potentiated by a sequential increase in the number of apoE receptor-binding domain repeats (trimer > dimer > monomer). We previously showed that the apoE dimer increased APP CTF in vivo; to determine whether the dimer also affected secreted APP or Abeta levels, we performed a single hippocampal injection of the apoE dimer in wild-type mice and analyzed its effect on APP processing. We found increased sAPPalpha and decreased Abeta levels at 24 hrs after treatment, suggesting that the apoE dimer may increase alpha-secretase cleavage.


CONCLUSIONS
These data suggest that small peptides consisting of tandem repeats of the apoE receptor-binding region are sufficient to alter APP trafficking and processing. The potency of these peptides increased with increasing repeats of the receptor binding domain of apoE. In addition, in vivo administration of the apoE peptide (dimer) increased sAPPalpha and decreased Abeta levels in wild-type mice. Overall, these findings contribute to our understanding of the effects of apoE on APP processing and Abeta production both in vitro and in vivo.
Minami
S Sakura
SS
Department of Neuroscience, Georgetown University, 3970 Reservoir Rd, NW, Washington, DC 20057, USA. map65@georgetown.edu.
Cordova
Antoinette
A
Cirrito
John R
JR
Tesoriero
Joseph A
JA
Babus
Lenard W
LW
Davis
Gary C
GC
Dakshanamurthy
Sivanesan
S
Turner
R Scott
RS
Pak
Daniel Ts
DTs
Rebeck
G William
GW
Paige
Mikell
M
Hoe
Hyang-Sook
HS
Brain Res Mol Brain Res. 2005 Jun 13;137(1-2):31-9
15950758
Glia. 2009 Mar;57(4):444-53
18803301
J Neurochem. 1999 Mar;72(3):1069-80
10037478
J Neurochem. 2005 Apr;93(1):145-55
15773914
Neuron. 2004 Apr 8;42(1):23-36
15066262
J Biol Chem. 1997 Mar 21;272(12):7977-82
9065468
Brain Res. 2006 Sep 27;1112(1):70-9
16905123
J Neurosci. 2007 Oct 3;27(40):10895-905
17913923
J Alzheimers Dis. 2006;9(3 Suppl):361-6
16914873
Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3922-7
10097139
Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):8098-102
8367470
Proc Natl Acad Sci U S A. 2005 Jan 25;102(4):1211-6
15657137
Brain Res. 1991 Feb 8;541(1):163-6
2029618
Biochemistry. 1999 Jul 27;38(30):9728-34
10423252
Neuron. 1995 Jul;15(1):219-28
7619525
J Biol Chem. 2006 Nov 24;281(47):36180-6
17012232
J Clin Invest. 1994 Aug;94(2):860-9
8040342
J Neurotrauma. 2007 Jul;24(7):1093-107
17610350
Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18700-5
16344478
Neurobiol Dis. 2002 Apr;9(3):305-18
11950276
J Neurochem. 2004 Sep;90(5):1132-43
15312168
J Biol Chem. 2000 Oct 27;275(43):33729-37
10924510
Nat Med. 2004 Jul;10(7):719-26
15195085
Microsc Res Tech. 2000 Aug 15;50(4):316-24
10936886
J Pharmacol Exp Ther. 2006 Sep;318(3):956-65
16740622
J Neurochem. 1998 Apr;70(4):1458-66
9523562
J Neurosci. 2007 Apr 11;27(15):4052-60
17428983
Neurotherapeutics. 2008 Jul;5(3):409-14
18625452
Brain Res. 2002 Nov 15;955(1-2):191-9
12419536
Biochem J. 2000 Jun 1;348 Pt 2:359-65
10816430
J Neurosci Res. 1997 Jul 1;49(1):9-18
9211985
Exp Neurol. 2005 Mar;192(1):109-16
15698624
Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2892-7
10694577
Neuron. 2008 Jun 12;58(5):681-93
18549781