 |
 Previous Article | Next Article 
The Journal of Neuroscience, May 1, 2002, 22(9):3445-3453
Neuronal Deficiency of Presenilin 1 Inhibits Amyloid Plaque
Formation and Corrects Hippocampal Long-Term Potentiation But Not a
Cognitive Defect of Amyloid Precursor Protein [V717I] Transgenic
Mice
Ilse
Dewachter1,
Delphine
Reversé2,
Nathalie
Caluwaerts1,
Laurence
Ris2,
Cuno
Kuipéri1,
Chris
Van den
Haute1,
Kurt
Spittaels1,
Lieve
Umans1,
Lutgarde
Serneels1,
Els
Thiry1,
Dieder
Moechars3,
Mark
Mercken3,
Emile
Godaux2, and
Fred
Van
Leuven1
1 Experimental Genetics Group, Katholieke
Universiteit Leuven, B-3000 Leuven, Belgium,
2 Laboratory of Neuroscience, University of Mons-Hainaut,
7000 Mons, Belgium, and 3 Janssen Research Foundation, 2340 Beerse, Belgium
In the brain of Alzheimer's disease (AD) patients, neurotoxic
amyloid peptides accumulate and are deposited as senile plaques. A
major therapeutic strategy aims to decrease production of amyloid peptides by inhibition of  -secretase. Presenilins are polytopic transmembrane proteins that are essential for -secretase activity during development and in amyloid production. By
loxP/Cre-recombinase-mediated deletion, we generated mice with
postnatal, neuron-specific presenilin-1 (PS1) deficiency, denoted
PS1(n /), that were viable and fertile, with normal brain
morphology. In adult PS1(n/) mice, levels of endogenous brain
amyloid peptides were strongly decreased, concomitant with accumulation
of amyloid precursor protein (APP) C-terminal fragments. In the
cross of APP[V717I]xPS1 (n/) double transgenic mice, the
neuronal absence of PS1 effectively prevented amyloid pathology, even
in mice that were 18 months old. This contrasted sharply with
APP[V717I] single transgenic mice that all develop amyloid pathology
at the age of 10-12 months. In APP[V717I]xPS1 (n/) mice,
long-term potentiation (LTP) was practically rescued at the end of the
2 hr observation period, again contrasting sharply with the strongly
impaired LTP in APP[V717I] mice. The findings demonstrate the
critical involvement of amyloid peptides in defective LTP in APP
transgenic mice. Although these data open perspectives for therapy of
AD by -secretase inhibition, the neuronal absence of PS1 failed to
rescue the cognitive defect, assessed by the object recognition test,
of the parent APP[V717I] transgenic mice. This points to potentially
detrimental effects of accumulating APP C99 fragments and demands
further study of the consequences of inhibition of -secretase
activity. In addition, our data highlight the complex functional
relation of APP and PS1 to cognition and neuronal plasticity in adult
and aging brain.
Key words:
PS1; Alzheimer's disease; neuronal plasticity; cognition; amyloid pathology; mouse model
Copyright © 2002 Society for Neuroscience 0270-6474/02/2293445-09$05.00/0
This article has been cited by other articles:
|
|
|
|
 
M. Townsend, Y. Qu, A. Gray, Z. Wu, T. Seto, M. Hutton, M. S. Shearman, and R. E. Middleton
Oral Treatment with a {gamma}-Secretase Inhibitor Improves Long-Term Potentiation in a Mouse Model of Alzheimer's Disease
J. Pharmacol. Exp. Ther.,
April 1, 2010;
333(1):
110 - 119.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. A. Harris, N. Devidze, B. Halabisky, I. Lo, M. T. Thwin, G.-Q. Yu, D. E. Bredesen, E. Masliah, and L. Mucke
Many Neuronal and Behavioral Impairments in Transgenic Mouse Models of Alzheimer's Disease Are Independent of Caspase Cleavage of the Amyloid Precursor Protein
J. Neurosci.,
January 6, 2010;
30(1):
372 - 381.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Y. Tamboli, K. Prager, D. R. Thal, K. M. Thelen, I. Dewachter, C. U. Pietrzik, P. St. George-Hyslop, S. S. Sisodia, B. De Strooper, M. T. Heneka, et al.
Loss of {gamma}-Secretase Function Impairs Endocytosis of Lipoprotein Particles and Membrane Cholesterol Homeostasis
J. Neurosci.,
November 12, 2008;
28(46):
12097 - 12106.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Terwel, D. Muyllaert, I. Dewachter, P. Borghgraef, S. Croes, H. Devijver, and F. Van Leuven
Amyloid Activates GSK-3{beta} to Aggravate Neuronal Tauopathy in Bigenic Mice
Am. J. Pathol.,
March 1, 2008;
172(3):
786 - 798.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Muyllaert, D. Terwel, A. Kremer, K. Sennvik, P. Borghgraef, H. Devijver, I. Dewachter, and F. Van Leuven
Neurodegeneration and Neuroinflammation in cdk5/p25-Inducible Mice: A Model for Hippocampal Sclerosis and Neocortical Degeneration
Am. J. Pathol.,
February 1, 2008;
172(2):
470 - 485.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Sennvik, K. Boekhoorn, R. Lasrado, D. Terwel, S. Verhaeghe, H. Korr, C. Schmitz, T. Tomiyama, H. Mori, H. Krugers, et al.
Tau-4R suppresses proliferation and promotes neuronal differentiation in the hippocampus of tau knockin/knockout mice
FASEB J,
July 1, 2007;
21(9):
2149 - 2161.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H.-g. Lee, X. Zhu, R. J. Castellani, A. Nunomura, G. Perry, and M. A. Smith
Amyloid-beta in Alzheimer Disease: The Null versus the Alternate Hypotheses
J. Pharmacol. Exp. Ther.,
June 1, 2007;
321(3):
823 - 829.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Saganich, B. E. Schroeder, V. Galvan, D. E. Bredesen, E. H. Koo, and S. F. Heinemann
Deficits in Synaptic Transmission and Learning in Amyloid Precursor Protein (APP) Transgenic Mice Require C-Terminal Cleavage of APP
J. Neurosci.,
December 27, 2006;
26(52):
13428 - 13436.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Wang, B. Wang, W. He, and H. Zheng
Wild-type Presenilin 1 Protects against Alzheimer Disease Mutation-induced Amyloid Pathology
J. Biol. Chem.,
June 2, 2006;
281(22):
15330 - 15336.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Deng, L. Tarassishin, V. Kallhoff, E. Peethumnongsin, L. Wu, Y.-M. Li, and H. Zheng
Deletion of presenilin 1 hydrophilic loop sequence leads to impaired gamma-secretase activity and exacerbated amyloid pathology.
J. Neurosci.,
April 5, 2006;
26(14):
3845 - 3854.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Boekhoorn, D. Terwel, B. Biemans, P. Borghgraef, O. Wiegert, G. J. A. Ramakers, K. de Vos, H. Krugers, T. Tomiyama, H. Mori, et al.
Improved long-term potentiation and memory in young tau-P301L transgenic mice before onset of hyperphosphorylation and tauopathy.
J. Neurosci.,
March 29, 2006;
26(13):
3514 - 3523.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Van Dooren, D. Muyllaert, P. Borghgraef, A. Cresens, H. Devijver, I. Van der Auwera, S. Wera, I. Dewachter, and F. Van Leuven
Neuronal or Glial Expression of Human Apolipoprotein E4 Affects Parenchymal and Vascular Amyloid Pathology Differentially in Different Brain Regions of Double- and Triple-Transgenic Mice
Am. J. Pathol.,
January 1, 2006;
168(1):
245 - 260.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Wines-Samuelson and J. Shen
Presenilins in the Developing, Adult, and Aging Cerebral Cortex
Neuroscientist,
October 1, 2005;
11(5):
441 - 451.
[Abstract]
[PDF]
|
|
|
|
|
|
|
C. A. Saura, G. Chen, S. Malkani, S.-Y. Choi, R. H. Takahashi, D. Zhang, G. K. Gouras, A. Kirkwood, R. G. M. Morris, and J. Shen
Conditional Inactivation of Presenilin 1 Prevents Amyloid Accumulation and Temporarily Rescues Contextual and Spatial Working Memory Impairments in Amyloid Precursor Protein Transgenic Mice
J. Neurosci.,
July 20, 2005;
25(29):
6755 - 6764.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Terwel, R. Lasrado, J. Snauwaert, E. Vandeweert, C. Van Haesendonck, P. Borghgraef, and F. Van Leuven
Changed Conformation of Mutant Tau-P301L Underlies the Moribund Tauopathy, Absent in Progressive, Nonlethal Axonopathy of Tau-4R/2N Transgenic Mice
J. Biol. Chem.,
February 4, 2005;
280(5):
3963 - 3973.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Willem, I. Dewachter, N. Smyth, T. Van Dooren, P. Borghgraef, C. Haass, and F. Van Leuven
{beta}-Site Amyloid Precursor Protein Cleaving Enzyme 1 Increases Amyloid Deposition in Brain Parenchyma but Reduces Cerebrovascular Amyloid Angiopathy in Aging BACE x APP[V717I] Double-Transgenic Mice
Am. J. Pathol.,
November 1, 2004;
165(5):
1621 - 1631.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Etcheberrigaray, M. Tan, I. Dewachter, C. Kuiperi, I. Van der Auwera, S. Wera, L. Qiao, B. Bank, T. J. Nelson, A. P. Kozikowski, et al.
Therapeutic effects of PKC activators in Alzheimer's disease transgenic mice
PNAS,
July 27, 2004;
101(30):
11141 - 11146.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Tournoy, X. Bossuyt, A. Snellinx, M. Regent, M. Garmyn, L. Serneels, P. Saftig, K. Craessaerts, B. De Strooper, and D. Hartmann
Partial loss of presenilins causes seborrheic keratosis and autoimmune disease in mice
Hum. Mol. Genet.,
July 1, 2004;
13(13):
1321 - 1331.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Ris, I. Dewachter, D. Reverse, E. Godaux, and F. Van Leuven
Capacitative Calcium Entry Induces Hippocampal Long Term Potentiation in the Absence of Presenilin-1
J. Biol. Chem.,
November 7, 2003;
278(45):
44393 - 44399.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Sastre, I. Dewachter, G. E. Landreth, T. M. Willson, T. Klockgether, F. van Leuven, and M. T. Heneka
Nonsteroidal Anti-Inflammatory Drugs and Peroxisome Proliferator-Activated Receptor-{gamma} Agonists Modulate Immunostimulated Processing of Amyloid Precursor Protein through Regulation of {beta}-Secretase
J. Neurosci.,
October 29, 2003;
23(30):
9796 - 9804.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Herms, I. Schneider, I. Dewachter, N. Caluwaerts, H. Kretzschmar, and F. Van Leuven
Capacitive Calcium Entry Is Directly Attenuated by Mutant Presenilin-1, Independent of the Expression of the Amyloid Precursor Protein
J. Biol. Chem.,
January 17, 2003;
278(4):
2484 - 2489.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. J. Selkoe
Alzheimer's Disease Is a Synaptic Failure
Science,
October 25, 2002;
298(5594):
789 - 791.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
