Aberrant amyloid precursor protein (APP) processing in hereditary forms of Alzheimer disease caused by APP familial Alzheimer disease mutations can be rescued by mutations in the APP GxxxG motif.
The identification of hereditary familial Alzheimer disease (FAD) mutations in the amyloid precursor protein (APP) and presenilin-1 (PS1) corroborated the causative role of amyloid-beta peptides with 42 amino acid residues (Abeta42) in the pathogenesis of AD. Although most FAD mutations are known to increase Abeta42 levels, mutations within the APP GxxxG motif are known to lower Abeta42 levels by attenuating transmembrane sequence dimerization. Here, we show that aberrant Abeta42 levels of FAD mutations can be rescued by GxxxG mutations. The combination of the APP-GxxxG mutation G33A with APP-FAD mutations yielded a constant 60% decrease of Abeta42 levels and a concomitant 3-fold increase of Abeta38 levels compared with the Gly(33) wild-type as determined by ELISA. In the presence of PS1-FAD mutations, the effects of G33A were attenuated, apparently attributable to a different mechanism of PS1-FAD mutants compared with APP-FAD mutants. Our results contribute to a general understanding of the mechanism how APP is processed by the gamma-secretase module and strongly emphasize the potential of the GxxxG motif in the prevention of sporadic AD as well as FAD.
Munter
Lisa-Marie
LM
Institut für Chemie und Biochemie, Freie Universität Berlin, Thielallee 63, 14195 Berlin, Germany.
Botev
Anne
A
Richter
Luise
L
Hildebrand
Peter W
PW
Althoff
Veit
V
Weise
Christoph
C
Kaden
Daniela
D
Multhaup
Gerd
G
D000544:Alzheimer Disease / Q000378:metabolism*; D020816:Amino Acid Motifs; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D045744:Cell Line, Tumor; D019281:Dimerization; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D020022:Genetic Predisposition to Disease; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D053763:Presenilins / Q000737:chemistry; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014162:Transfection
D016564:Amyloid beta-Protein Precursor; D053763:Presenilins
Neuron. 2005 Jul 21;47(2):191-199
16039562
J Neurosci. 2009 Oct 14;29(41):13042-52
19828817
Biochemistry. 2002 Feb 26;41(8):2825-35
11851430
Dement Geriatr Cogn Disord. 2008;26(1):43-9
18587238
Nature. 1995 Aug 31;376(6543):775-8
7651536
J Neurochem. 2006 Apr;97(1):30-43
16515557
Biol Psychiatry. 2000 Feb 1;47(3):183-99
10682216
J Biol Chem. 2007 Apr 27;282(17):12388-96
17329245
Am J Hum Genet. 1992 Nov;51(5):998-1014
1415269
J Cell Sci. 2009 Feb 1;122(Pt 3):368-77
19126676
FEBS Lett. 1992 Aug 31;309(1):20-4
1511741
J Neurosci. 2005 Jan 12;25(2):436-45
15647487
Nature. 2001 Nov 8;414(6860):212-6
11700559
Nature. 1991 Oct 31;353(6347):844-6
1944558
Science. 1991 Oct 4;254(5028):97-9
1925564
Neurology. 2003 Jan 28;60(2):235-9
12552037
Neuron. 1996 Nov;17(5):1005-13
8938131
Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):4119-24
10097173
Nature. 1992 Dec 17;360(6405):672-4
1465129
EMBO J. 2007 Mar 21;26(6):1702-12
17332749
Ann Neurol. 2000 Feb;47(2):249-53
10665499
Science. 1992 Apr 10;256(5054):184-5
1566067
J Biol Chem. 2006 May 26;281(21):14776-86
16595682
Mol Cell. 2004 Aug 13;15(3):343-53
15304215
Nat Med. 1996 Aug;2(8):864-70
8705854
Hum Mol Genet. 1997 Nov;6(12):2087-9
9328472
Hum Mol Genet. 1995 Dec;4(12):2363-71
8634711
Nat Genet. 1992 Jun;1(3):218-21
1303239
J Biol Chem. 2003 Jul 4;278(27):24294-301
12707272
Hum Mol Genet. 2000 Nov 1;9(18):2589-98
11063718
J Biol Chem. 2001 Jun 15;276(24):21562-70
11279122
J Biol Chem. 2008 Jan 11;283(2):677-83
17962197
J Biol Chem. 2008 Mar 14;283(11):7271-9
18182389
J Biol Chem. 2008 Jun 20;283(25):17049-54
18426795
EMBO J. 2005 Oct 19;24(20):3624-34
16193067
J Neurochem. 2007 Mar;100(5):1234-46
17241131
Biochemistry. 2004 Oct 26;43(42):13532-40
15491160
BMC Neurosci. 2008 Jan 30;9:17
18234110
J Biol Chem. 2005 Nov 11;280(45):37689-97
16157587
Nat Struct Biol. 1999 Apr;6(4):327-31
10201399
Nature. 2008 Jun 12;453(7197):925-9
18548070
J Neurochem. 2009 Aug;110(4):1129-34
19457065
J Biol Chem. 2009 May 29;284(22):15016-25
19336403
J Biol Chem. 2001 Sep 7;276(36):33923-9
11438549
EMBO Rep. 2007 Feb;8(2):141-6
17268505