Inhibition of GSK-3 ameliorates Abeta pathology in an adult-onset Drosophila model of Alzheimer's disease.
Abeta peptide accumulation is thought to be the primary event in the pathogenesis of Alzheimer's disease (AD), with downstream neurotoxic effects including the hyperphosphorylation of tau protein. Glycogen synthase kinase-3 (GSK-3) is increasingly implicated as playing a pivotal role in this amyloid cascade. We have developed an adult-onset Drosophila model of AD, using an inducible gene expression system to express Arctic mutant Abeta42 specifically in adult neurons, to avoid developmental effects. Abeta42 accumulated with age in these flies and they displayed increased mortality together with progressive neuronal dysfunction, but in the apparent absence of neuronal loss. This fly model can thus be used to examine the role of events during adulthood and early AD aetiology. Expression of Abeta42 in adult neurons increased GSK-3 activity, and inhibition of GSK-3 (either genetically or pharmacologically by lithium treatment) rescued Abeta42 toxicity. Abeta42 pathogenesis was also reduced by removal of endogenous fly tau; but, within the limits of detection of available methods, tau phosphorylation did not appear to be altered in flies expressing Abeta42. The GSK-3-mediated effects on Abeta42 toxicity appear to be at least in part mediated by tau-independent mechanisms, because the protective effect of lithium alone was greater than that of the removal of tau alone. Finally, Abeta42 levels were reduced upon GSK-3 inhibition, pointing to a direct role of GSK-3 in the regulation of Abeta42 peptide level, in the absence of APP processing. Our study points to the need both to identify the mechanisms by which GSK-3 modulates Abeta42 levels in the fly and to determine if similar mechanisms are present in mammals, and it supports the potential therapeutic use of GSK-3 inhibitors in AD.
Sofola
Oyinkan
O
Department of Genetics, Evolution, and Environment, Institute of Healthy Ageing and Research, University College London, London, United Kingdom.
Kerr
Fiona
F
Rogers
Iain
I
Killick
Richard
R
Augustin
Hrvoje
H
Gandy
Carina
C
Allen
Marcus J
MJ
Hardy
John
J
Lovestone
Simon
S
Partridge
Linda
L
D000375:Aging / Q000187:drug effects / Q000473:pathology*; D000544:Alzheimer Disease / Q000201:enzymology* / Q000401:mortality / Q000473:pathology* / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000187:drug effects / Q000201:enzymology*; D005799:Genes, Dominant / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008094:Lithium / Q000494:pharmacology; D050505:Mutant Proteins / Q000633:toxicity; D009420:Nervous System / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D010455:Peptides / Q000633:toxicity; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D029721:Drosophila Proteins; D050505:Mutant Proteins; D010455:Peptides; D016875:tau Proteins; D010768:Phosphoserine; D008094:Lithium; C080335:Sgg protein, Drosophila; D038362:Glycogen Synthase Kinase 3
Annu Rev Pharmacol Toxicol. 2003;43:545-84
12415125
EMBO J. 2001 Jan 15;20(1-2):27-39
11226152
J Biol Chem. 2008 Jul 4;283(27):19066-76
18463098
Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6623-8
15069204
Curr Top Dev Biol. 1999;43:153-90
9891886
Semin Cell Dev Biol. 1998 Dec;9(6):619-25
10075489
Am J Pathol. 2007 May;170(5):1669-75
17456772
J Neurosci. 2005 Nov 23;25(47):10960-9
16306409
Nat Neurosci. 2001 Sep;4(9):887-93
11528419
Cell. 2004 Mar 5;116(5):671-82
15006350
Hum Mol Genet. 2010 Aug 1;19(15):2947-57
20466736
Cell. 1997 Apr 18;89(2):297-308
9108484
Science. 2001 May 25;292(5521):1550-2
11375493
Am J Pathol. 2008 Mar;172(3):786-98
18258852
Proc Natl Acad Sci U S A. 2003 May 13;100(10):6221-6
12732730
Mol Cell Neurosci. 2004 Jul;26(3):365-75
15234342
Invert Neurosci. 2007 Sep;7(3):165-71
17636367
J Neurosci. 2003 Oct 1;23(26):8867-71
14523088
Biochem Biophys Res Commun. 2001 Jan 26;280(3):720-5
11162580
Development. 2003 Sep;130(17):3965-75
12874119
Genesis. 2002 Sep-Oct;34(1-2):99-102
12324959
J Biol Chem. 2007 Aug 10;282(32):23645-54
17562708
FEBS Lett. 1992 Dec 21;314(3):315-21
1334849
Trends Mol Med. 2009 Mar;15(3):112-9
19246243
J Cell Mol Med. 2009 Mar;13(3):412-21
19374683
J Neurogenet. 1984 Dec;1(4):289-313
6443123
Nature. 2003 May 22;423(6938):435-9
12761548
Mol Cell Proteomics. 2006 Apr;5(4):749-57
16340016
Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4162-7
12634421
J Neurophysiol. 1980 Aug;44(2):405-21
6774064
Curr Biol. 2004 Apr 6;14(7):599-605
15062101
Science. 2001 Aug 24;293(5534):1487-91
11520987
Neuron. 2002 May 16;34(4):509-19
12062036
Science. 2001 Aug 24;293(5534):1491-5
11520988
J Neurosci. 1999 Nov 1;19(21):9374-84
10531442
FASEB J. 2004 May;18(7):902-4
15033922
Nature. 1993 Apr 8;362(6420):557-60
8385271
FEBS Lett. 2010 Jul 2;584(13):2916-20
20493190
Methods Enzymol. 2006;412:234-55
17046662
J Neurosci. 2003 Jul 2;23(13):5645-9
12843267
Neurosci Lett. 1992 Nov 23;147(1):58-62
1336152
Cell Mol Life Sci. 2007 Aug;64(15):1930-44
17530463
Science. 2006 Sep 15;313(5793):1604-10
16902091
Neuroreport. 1997 Oct 20;8(15):3251-5
9351652
Mol Cell Biol. 1998 Nov;18(11):6624-33
9774677
Mol Psychiatry. 2004 May;9(5):522-30
14993907
Am J Hum Genet. 1999 Feb;64(2):414-21
9973279
Mol Cell Biol. 2004 Jun;24(11):4909-19
15143183
Neuroscience. 2005;130(2):339-47
15664690
J Biol Chem. 2003 Jan 24;278(4):2081-4
12464614
Development. 2008 Mar;135(6):1081-8
18256197
Biochem Biophys Res Commun. 2005 Dec 2;337(4):1097-101
16226718
NeuroRx. 2005 Jul;2(3):423-37
16389306
J Neurosci. 2007 Feb 21;27(8):1981-91
17314294
J Neurochem. 2006 Aug;98(4):1167-75
16762022
Neuron. 2004 Aug 5;43(3):321-32
15294141
Exp Neurol. 2010 Jun;223(2):401-9
19782075
Sci STKE. 2004 Feb 12;2004(220):pl6
14970377
Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8745-50
10411946
Genes Brain Behav. 2008 Feb;7 Suppl 1:57-66
18184370
J Neurosci. 2007 Mar 7;27(10):2483-92
17344386
Learn Mem. 2004 May-Jun;11(3):277-87
15169857
Nature. 1998 Jun 18;393(6686):702-5
9641683
Neurobiol Dis. 2010 Mar;37(3):622-9
20004245
Science. 2007 May 4;316(5825):750-4
17478722
Biochemistry. 2004 Jun 8;43(22):6899-908
15170327
Trends Genet. 2006 May;22(5):281-9
16567017
Neuron. 2003 Dec 18;40(6):1087-93
14687544
Biochem Biophys Res Commun. 2009 Aug 14;386(1):257-62
19523444
J Neurochem. 2007 Aug;102(4):1053-63
17472708
Neuroscience. 2005;132(1):123-35
15780472
Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12596-601
11675495
Proc Natl Acad Sci U S A. 2005 May 10;102(19):6990-5
15867159
Mol Cell. 2006 Nov 17;24(4):627-33
17188038
Science. 2001 Jul 27;293(5530):711-4
11408621
Exp Gerontol. 1978;13(3-4):189-96
99324
Semin Cell Dev Biol. 2006 Feb;17(1):31-41
16378740
Curr Biol. 1994 Dec 1;4(12):1077-86
7704571
Proc Natl Acad Sci U S A. 1989 Apr;86(7):2478-82
2494667
Nature. 2000 Mar 23;404(6776):394-8
10746727