Memory impairment in transgenic Alzheimer mice requires cellular prion protein.
Soluble oligomers of the amyloid-beta (Abeta) peptide are thought to play a key role in the pathophysiology of Alzheimer's disease (AD). Recently, we reported that synthetic Abeta oligomers bind to cellular prion protein (PrP(C)) and that this interaction is required for suppression of synaptic plasticity in hippocampal slices by oligomeric Abeta peptide. We hypothesized that PrP(C) is essential for the ability of brain-derived Abeta to suppress cognitive function. Here, we crossed familial AD transgenes encoding APPswe and PSen1DeltaE9 into Prnp-/- mice to examine the necessity of PrP(C) for AD-related phenotypes. Neither APP expression nor Abeta level is altered by PrP(C) absence in this transgenic AD model, and astrogliosis is unchanged. However, deletion of PrP(C) expression rescues 5-HT axonal degeneration, loss of synaptic markers, and early death in APPswe/PSen1DeltaE9 transgenic mice. The AD transgenic mice with intact PrP(C) expression exhibit deficits in spatial learning and memory. Mice lacking PrP(C), but containing Abeta plaque derived from APPswe/PSen1DeltaE9 transgenes, show no detectable impairment of spatial learning and memory. Thus, deletion of PrP(C) expression dissociates Abeta accumulation from behavioral impairment in these AD mice, with the cognitive deficits selectively requiring PrP(C).
Gimbel
David A
DA
Cellular Neuroscience, Neurodegeneration, and Repair Program, Yale University School of Medicine, New Haven, Connecticut 06536, USA.
Nygaard
Haakon B
HB
Coffey
Erin E
EE
Gunther
Erik C
EC
Laurén
Juha
J
Gimbel
Zachary A
ZA
Strittmatter
Stephen M
SM
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001362:Avoidance Learning; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018782:Maze Learning; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000235:genetics*; D018621:PrPC Proteins / Q000235:genetics / Q000502:physiology*; D053764:Presenilin-1 / Q000235:genetics; D011897:Random Allocation; D012701:Serotonin / Q000378:metabolism; D016019:Survival Analysis
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018621:PrPC Proteins; D053764:Presenilin-1; D012701:Serotonin
Neuroscience. 2003;120(3):705-20
12895511
J Neurosci. 2000 Jun 1;20(11):4050-8
10818140
Proc Natl Acad Sci U S A. 1998 May 26;95(11):6448-53
9600986
Science. 2003 Oct 31;302(5646):871-4
14593181
J Neurosci. 1999 Jun 15;19(12):4867-80
10366621
J Neurosci. 2006 Dec 20;26(51):13279-86
17182778
J Neurosci. 2004 May 12;24(19):4692-7
15140940
J Comp Physiol Psychol. 1966 Oct;62(2):222-6
5969601
J Neuropathol Exp Neurol. 1992 Jul;51(4):404-14
1619440
J Neurosci. 2009 Mar 18;29(11):3453-62
19295151
Hum Mol Genet. 2004 Jan 15;13(2):159-70
14645205
Nat Neurosci. 1999 Mar;2(3):271-6
10195221
Nature. 1996 Jan 25;379(6563):339-43
8552188
Neuron. 2004 Oct 28;44(3):439-51
15504325
Neurobiol Aging. 2010 Jul;31(7):1173-87
18790549
Behav Brain Res. 2001 Dec 14;127(1-2):159-81
11718890
Nat Protoc. 2006;1(2):848-58
17406317
J Neurosci. 2004 Nov 17;24(46):10511-20
15548666
J Neurosci. 2003 May 1;23(9):3837-43
12736354
J Neurosci. 2009 Nov 11;29(45):14108-19
19906959
EMBO J. 2007 Jan 24;26(2):548-58
17245437
J Neurosci Methods. 1984 May;11(1):47-60
6471907
Am J Pathol. 2000 Dec;157(6):2003-10
11106573
J Neurosci. 2000 Jan 15;20(2):771-82
10632606
Science. 2005 Jun 3;308(5727):1435-9
15933194
Neurobiol Aging. 1990 Jan-Feb;11(1):29-37
2325814
Neurobiol Aging. 2005 Aug-Sep;26(8):1177-82
15917101
Nat Med. 2008 Aug;14(8):837-42
18568035
Nature. 2002 Apr 4;416(6880):535-9
11932745
Neuron. 2007 Sep 6;55(5):697-711
17785178
Mol Neurobiol. 1994 Apr-Jun;8(2-3):121-7
7999308
J Neurosci. 2001 Jul 1;21(13):4691-8
11425896
Brain Res. 1999 Sep 4;840(1-2):23-35
10517949
Mol Cell Neurosci. 2005 May;29(1):26-39
15866044
J Neurosci. 2005 Oct 5;25(40):9096-101
16207868
Nature. 1997 May 29;387(6632):500-5
9168112
EMBO J. 2007 Jan 24;26(2):538-47
17245436
Nature. 2006 Mar 16;440(7082):352-7
16541076
Nature. 2000 Dec 21-28;408(6815):975-9
11140684
Nat Neurosci. 2005 Jan;8(1):79-84
15608634
J Neurosci. 2008 Dec 17;28(51):13805-14
19091971
J Neurosci. 2009 Dec 2;29(48):15266-76
19955379
Nature. 2009 Jul 30;460(7255):632-6
19641596
Science. 1966 Jul 1;153(3731):25-33
5328120
J Neurol Sci. 1987 Apr;78(2):151-64
3572454
Prion. 2009 Oct-Dec;3(4):240-9
19901559
Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3228-33
10077666
J Neurosci Methods. 2006 Sep 15;155(2):172-9
16469388
Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3502-6
19204288
Nat Biotechnol. 2004 Jun;22(6):724-31
15146195
Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):11062-7
17573534
Ann Neurol. 2004 Jun;55(6):801-14
15174014
J Neurotrauma. 2009 Jan;26(1):81-95
19125588
Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2295-300
20133875
Neurobiol Dis. 2004 Mar;15(2):188-95
15006688
Nature. 2009 Feb 26;457(7233):1128-32
19242475
J Biol Chem. 1999 Mar 5;274(10):6483-92
10037741
Science. 2007 May 4;316(5825):750-4
17478722
Neuroscience. 2002;114(3):807-15
12220580
Nature. 2002 May 30;417(6888):547-51
12037567
Ann Neurol. 2006 Nov;60(5):540-9
16958113
Neuron. 2009 Mar 12;61(5):734-49
19285470