A study of long-term potentiation in transgenic mice over-expressing mutant forms of both amyloid precursor protein and presenilin-1.
ABSTRACT Synaptic transmission and long-term potentiation (LTP) in the CA1 region of hippocampal slices have been studied during ageing of a double transgenic mouse strain relevant to early-onset familial Alzheimer's disease (AD). This strain, which over-expresses both the 695 amino acid isoform of human amyloid precursor protein (APP) with K670N and M671L mutations and presenilin 1 with the A246E mutation, has accelerated amyloidosis and plaque formation. There was a decrease in synaptic transmission in both wildtype and transgenic mice between 2 and 9 months of age. However, preparing slices from 14 month old animals in kynurenic acid (1 mM) counteracted this age-related deficit. Basal transmission and paired-pulse facilitation was similar between the two groups at all ages (2, 6, 9 and 14 months) tested. Similarly, at all ages LTP, induced either by theta burst stimulation or by multiple tetani, was normal. These data show that a prolonged, substantially elevated level of Abeta are not sufficient to cause deficits in the induction or expression of LTP in the CA1 hippocampal region.
- SourceAvailable from: medicine.mcgill.ca[show abstract] [hide abstract]
ABSTRACT: The presenilin 1 and presenilin 2 genes have been identified as pathogenic loci involved in the majority of early onset, autosomal dominant Alzheimer's disease. A series of (predominantly) missense mutations have been identified in the two genes which lead to disease. The presenilins are probably eight transmembrane domain proteins with both termini in the cytoplasmic compartment. They have a wide tissue distribution and are found in the endoplasmic reticulum and early Golgi. The mechanism of pathogenesis of the mutations is not clear although, both in patients and in in vitro systems, the effects of presenilin mutations are reminiscent of the effects of the pathogenic mutations in the amyloid precursor protein gene which lead to increases in the amount of amyloid-beta42(43) being produced from the metabolism of the amyloid protein precursor. Thus, the presenilin data provide independent support for the amyloid cascade hypothesis of Alzheimer's pathogenesis. Work on the Caenorhabditis elegans homologues of the presenilins, spe-4 and sel-12, suggests that the presenilins may have a more general and direct role in the processing and trafficking of membrane-bound proteins and that, in part, the pathogenic mutations may disrupt this role.Human Molecular Genetics 02/1997; 6(10):1639-46. · 7.69 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: The most common cause of dementia occurring in mid- to late-life is Alzheimer's disease (AD). Some cases of AD, particularly those of early onset, are familial and inherited as autosomal dominant disorders linked to the presence of mutant genes that encode the amyloid precursor protein (APP) or the presenilins (PS1 or PS2). These mutant gene products cause dysfunction/death of vulnerable populations of nerve cells important in memory, higher cognitive processes, and behavior. AD affects 7-10% of individuals > 65 years of age and perhaps 40% of individuals > 80 years of age. For the late-onset cases, the principal risk factors are age and apolipoprotein (apoE) allele type, with apoE4 allele being a susceptibility factor. In this review, we briefly discuss the clinical syndrome of AD and the neurobiology/neuropathology of the disease and then focus attention on mutant genes linked to autosomal dominant familial AD (FAD), the biology of the proteins encoded by these genes, and the recent exciting progress in investigations of genetically engineered animal models that express these mutant genes and develop some features of AD.Annual Review of Neuroscience 01/1998; 21:479-505. · 20.61 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Alzheimer's disease is the most prevalent form of dementia. Neuropathogenesis is proposed to be a result of the accumulation of amyloid beta peptides in the brain together with oxidative stress mechanisms and neuroinflammation. The presenilin proteins are central to the gamma-secretase cleavage of the amyloid prescursor protein (APP), releasing the amyloid beta peptide. Point mutations in the presenilin genes lead to cases of familial Alzheimer's disease by increasing APP cleavage resulting in excess amyloid beta formation. This review discusses the molecular mechanism of Alzheimer's disease with a focus on the presenilin genes. Alternative splicing of transcripts from these genes and how these may function in several disease states is discussed. There is an emphasis on the importance of animal models in elucidating the molecular mechanisms behind the development of Alzheimer's disease and how the zebrafish, Danio rerio, can be used as a model organism for analysis of presenilin function and Alzheimer's disease pathogenesis.Biochimica et Biophysica Acta 04/2007; 1772(3):285-97. · 4.66 Impact Factor
Fitzjohn et al. Molecular Brain 2010, 3:21
A study of long-term potentiation in transgenic
mice over-expressing mutant forms of both
amyloid precursor protein and presenilin-1
© 2010 Fitzjohn et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
Stephen M Fitzjohn*1, Frederick Kuenzi1,2, Robin A Morton1,2, Thomas W Rosahl2,3, Huw Lewis2, David Smith2,
Guy R Seabrook2,4 and Graham L Collingridge1
Synaptic transmission and long-term potentiation (LTP) in the CA1 region of hippocampal slices have been studied
during ageing of a double transgenic mouse strain relevant to early-onset familial Alzheimer's disease (AD). This strain,
which over-expresses both the 695 amino acid isoform of human amyloid precursor protein (APP) with K670N and
M671L mutations and presenilin 1 with the A246E mutation, has accelerated amyloidosis and plaque formation. There
was a decrease in synaptic transmission in both wildtype and transgenic mice between 2 and 9 months of age.
However, preparing slices from 14 month old animals in kynurenic acid (1 mM) counteracted this age-related deficit.
Basal transmission and paired-pulse facilitation was similar between the two groups at all ages (2, 6, 9 and 14 months)
tested. Similarly, at all ages LTP, induced either by theta burst stimulation or by multiple tetani, was normal. These data
show that a prolonged, substantially elevated level of Aβ are not sufficient to cause deficits in the induction or
expression of LTP in the CA1 hippocampal region.
Three loci have been identified that account for nearly all
the familial Alzheimer's disease (AD) cases. Mutations in
the amyloid precursor protein (APP) gene account for
around 2-3% percent of familial AD cases and mutations
in presenilins 1 and 2 (PS1 and PS2) have been linked to
70-80% of early onset AD [1-3]. The mutations associated
with early onset familial AD in a Swedish family, where
the 695 amino acid APP protein contains the two muta-
tions K670N and M671L (APP695SWE mutation), affect
cleavage of APP at the β-secretase site . Subsequent
cleavage of APP at the intramembranous γ-secretase site
results in the formation of Aβ. PS1 is intimately associ-
ated with the cleavage of APP at the γ-secretase site and
familial AD mutations in PS1, such as the A246E muta-
tion occurring in transmembrane domain 6 of the prese-
nilin protein [5,6], alter the efficiency of cleavage of APP
and accelerate the production of Aβ [3,6-8].
Mice expressing the human form of the APP695SWE
mutation develop certain AD-like symptoms, such as
increased Aβ deposits and plaques, increased glial cell
number, and deficits in spatial memory learning tasks [9-
12]. Physiological studies have focused on the hippocam-
pus, a region affected by AD, and have studied, in partic-
ular, long-term potentiation (LTP) as a candidate synaptic
mechanism involved in learning and memory . How-
ever, the findings have been controversial. Thus, one
study reported normal synaptic transmission but
impaired LTP in the APP695SWE mutant  whilst in
other studies synaptic transmission was impaired but
LTP was normal in the mutant [14,15]. In contrast, mice
expressing the PS1A246E mutation showed enhanced LTP
, along with increased production of Aβ(42), the lon-
ger form of Aβ associated with plaque formation .
Mice expressing mutations in both APP and PS1 exhibit
accelerated Aβ production compared to those carrying
mutations in only APP or PS1 . Studies using double
transgenic (DbTg) mice expressing both the APP695SWE
mutations in APP and either the PS1M146L  or PS1P264L
 mutation showed reduced hippocampal LTP at a
younger age than basal synaptic transmission was com-
* Correspondence: email@example.com
1 MRC Centre for Synaptic Plasticity, Department of Anatomy, University of
Bristol, University Walk, Bristol, BS8 1TD, UK
Full list of author information is available at the end of the article
Fitzjohn et al. Molecular Brain 2010, 3:21
Page 2 of 9
promised. However, a recent study found no alteration in
hippocampal synaptic transmission or plasticity in mice
overexpressing the APP695SWE and PS1ΔE9 mutations,
even though the mice showed deficits in spatial learning
. Another DbTg strain of mouse which over-expresses
both the 695 amino acid isoform of human amyloid pre-
cursor protein (APP) with K670N and M671L mutations
(APP695SWE mice) and the A246E mutation in PS1
(PS1A246E) has much more aggressive amyloidosis and
plaque deposition than the APP695SWE mice . Given
the relevance of these mouse models to human disease
but the conflicting findings of the effect of double muta-
tions on synaptic transmission and plasticity in the hip-
pocampus, we report here an analysis of these DbTg
The generation of the APP695SWE transgenic mice used
in this study has been described previously [9,22].
APP695SWE transgenic mice were originally in a hybrid
87.5% C57BL6 x 12.5% SJL genetic background and were
subsequently backcrossed to C57BL6 x SJL F1 mice over
several generations. APP695SWE transgenic mice in a
background closer to 50% C57BL6-50% SJL were then
crossed with the PS1A246E transgenic line overexpressing
the familial AD PS1A246E mutation of human PS1  to
generate the DbTg line (APP695SWE x PS1A246E; Lewis et
al, 2004). All animals used in this study were from the N4
generation. All procedures were carried out in accor-
dance with The UK Animals (Scientific Procedures) Act
Four age groups were studied: 2 months (i.e., between 2
and 3 months of age), 6 (6-7), 9 (9-10) and 14 (14 -15)
months of age. Mice older than 15 months were not stud-
ied because of their high mortality and ethical consider-
ations. All mice in this study were either heterozygous for
both the APP695SWE and PS1A246E transgene (DbTg) or
their wildtype (Wt) littermates. Animals were genotyped
using PCR based methods for detection of the
APP695SWE transgene [9,14,22], the PS1A246E transgene
 and for the rd (retinal degeneration) mutation .
Rd homozygous mice were excluded from this study as a
precaution, since it has been suggested that this mutation
may indirectly affect neuronal number within the hip-
pocampus . All experiments and analyses were per-
formed with the experimenters blind as to the genotype
of the animal.
Quantification of Aβ levels by HTRF
Levels of Aβ were determined by homogenous time-
resolved fluorescence (HTRF) immunoassay as described
previously . Amyloid was extracted from the contral-
ateral hemispheres by homogenisation in 10 volumes of 5
M GnHCl, 50 mM HEPES (pH 7.3), 5 mM EDTA plus 1x
protease inhibitor cocktail (Complete™, obtained from
Roche Diagnostics). Following 3 h rotation at room tem-
perature, the homogenate was diluted ten-fold into ice-
cold 25 mM HEPES (pH 7.3), 1 mM EDTA, 0.1% BSA
plus 1x protease inhibitor cocktail and centrifuged
(16,000g, 20 min, 4°C). Aliquots of the supernatant were
stored at -20°C. The levels of amyloid peptides Aβ(40)
and Aβ(42) were then detected by HTRF. All peptides (of
> 95% purity; California Peptide Research Inc., California,
U.S.A.) were frozen at 100 μM in 100% DMSO and seri-
ally diluted in buffer whose composition reflects that of
the extracted samples (1 part GnHCl extraction buffer: 9
parts dilution buffer, as above). The HTRF signal was
generated as a result of non-radiative transfer from euro-
pium cryptate-labelled Aβ (40)- or Aβ (42)-specific anti-
bodies (G2-10 and G2-11 respectively; licensed from the
University of Heidelberg; labelled at CIS bio interna-
tional, Marcoule, France) to streptavidin-conjugated APC
(Prozyme). The latter was brought into the complex by
interaction with biotinylated antibody 4G8 (Senetek plc,
Missouri, U.S.A.), which is specific for residues 17-24 of
Aβ. Final reagent concentrations in a typical 96-well plate
assay were: G2-10K (0.75 nM) or G2-11K (0.6 nM), 4G8
+/- biotin (1.0 nM), SA-XL665 (2.0 nM), KF (0.1-0.2 M).
50 μl of sample or synthetic peptide standard were
assayed and a total volume of 200 μl/well was made up
with dilution buffer. Blank values were determined by the
use of non-biotinylated 4G8 antibody. The reaction mix-
ture was left at 4°C for 20 h, and then read on the Discov-
ery™ HTRF microplate analyser, providing simultaneous
measurement at 665 nm (XL665 fluorescence) and 620
nm (EuK fluorescence). The ΔR ratio [= Ratio (sample) -
Ratio (blank)] was used to extrapolate the amyloid con-
centrations of the brain extracts from the synthetic pep-
tide standard curves.
Histology to demonstrate plaque deposition was per-
formed as described previously (Lewis et al, 2004).
Briefly, 6 μm sagittal hippocampal slices were prepared
and monoclonal anti-human β-amyloid (clone 6F3D)
(DAKO, UK) was used to demonstrate amyloid plaques
whilst polyclonal anti-GFAP (glial fibrillary acidic pro-
tein: DAKO) used to label reactive astrocytes. Endoge-
nous peroxidase activity was blocked in 0.3% H2O2 in 0.1
M pH 7.4 phosphate buffered saline (PBS) for 30 min;
non-specific binding was blocked by incubation with 5%
normal horse serum (5% NHS) (Vector Labs, UK) in PBS
for 1 h. Mouse anti-β-amyloid was applied (1:100 in 5%
NHS) overnight at 4°C. Biotinylated anti-mouse IgG
(Vector Labs) was applied for 30 min, followed by ABC
reagent (Vector Elite, Vector Labs) for 30 min. DAB
Fitzjohn et al. Molecular Brain 2010, 3:21
Page 3 of 9
(Menarini, UK) was used as the chromogenic substrate.
Peroxidase activity was quenched in 0.3% H2O2/PBS and
sections further incubated in polyclonal anti-GFAP
(1:1000 in 5% normal goat serum) overnight at 4°C. Visu-
alisation was achieved by incubation in biotinylated anti-
rabbit IgG followed by ABC reagent (Vector Elite, Vector
Recordings were made form 350 μm thick hippocampal
slices prepared from 2, 6, 9 and 14 month old DbTg and
Wt mice. Animals were killed by decapitation, as licensed
under the UK Animals (Scientific Procedures) Act 1986,
and the brains rapidly removed in ice-cold artificial cere-
brospinal fluid (aCSF). The composition of this aCSF
was, in mM: NaCl, 126; NaH2PO4, 1.2; MgCl2, 1.3; CaCl2,
2.4; KCl, 2.5; NaHCO3, 26; glucose, 10. Brains were cut
along the midline and parasagittal whole brain slices pre-
pared from one hemisphere (randomly chosen) using a
Vibratome. The hippocampus was then dissected out of
these slices. The contralateral hemisphere was used for
histology or determination of Aβ levels. Slices were
allowed to recover for at least 1 h at room temperature
before being transferred to a submerged recording cham-
ber perfused with aCSF at 2 ml.min.-1 and maintained at
33°C. Kynurenic acid (1 mM) was included in the aCSF
used for preparing slices from the 14 month old animals.
Slices were then transferred to non-kynurenic acid con-
taining aCSF approximately 30 min after dissection and
allowed to recover for a further 30 min.
Field excitatory postsynaptic potentials (fEPSPs) were
recorded from stratum radiatum of area CA1 and Schaf-
fer collateral-commissural fibres were stimulated using a
bipolar nickel-chromium electrode. The initial slope of
the negative-going phase of the fEPSP was used as a mea-
sure of synaptic efficacy. Recordings were made using a
SPIKE 2 script running on a CED1401plus interface
(Cambridge Electronic Design).
curves were constructed by using stimulus intensities
from 0 to 45 V in increments of 5 V. Responses were sub-
sequently set to a level that gave a slope value of approxi-
mately 20% of the maximum obtained. Baseline responses
were obtained every 30 s. Paired-pulse facilitation (PPF)
was assessed using a succession of paired-pulses using
inter-pulse intervals of 25, 50, 100, 200 and 300 ms. A fur-
ther 30 min baseline period was obtained before attempt-
ing to induce LTP.
LTP was induced by delivery of a theta burst stimula-
tion paradigm (TBS), which comprised 10 bursts, at an
interburst frequency of 5 Hz and an intraburst frequency
of 100 Hz, each burst consisting of 4 stimuli delivered at
test stimulus intensity. In some experiments, LTP was
induced using a stronger stimulation whereby a repetitive
tetanic stimulus was applied (100 stimuli at 100 Hz at test
intensity repeated 4 times at 5 min intervals). All data are
presented as mean ± s.e.mean. n values are given as [x (y)]
where x = number of slices and y = number of animals.
Data were log transformed and analysed using a one-way
ANOVA with repeated measures (BMDP statistical pack-
age, release 7). Linear regression of fEPSP slope vs fibre
volley amplitude was done with Microsoft® Excel 97 Anal-
Aβ levels and amyloid plaque deposition
Expression of the APP695SWE x PS1A246E transgenes pro-
duced a dramatic increase in both short (Aβ(40)) and
long (Aβ(42)) forms of the Aβ peptide (Fig. 1). This eleva-
tion in Aβ levels occurred several months earlier than in
the single APP695SWE transgenic [14,26]. At 9 months,
the Aβ load was significantly greater than in Wt brains;
levels of Aβ(40) were 3.0 ± 0.5 compared with 0.03 ± 0.02
nmol/g wet weight tissue and levels of Aβ(42) were 1.6 ±
0.4 compared to 0.01 ± 0.009 nmol/g wet weight tissue, in
DbTg and Wt mice, respectively. At 14 months the levels
of Aβ(40) and Aβ(42) increased to 10.8 ± 2.2 and 5.6 ± 1.4
nmol/g wet weight tissue in DbTg mice, compared to 0.01
Figure 1 Plaques and elevated levels of Aβ(40) and Aβ(42) in
DbTg (Tg) mice. (A) Example hippocampal slices from 14 month old
animals, illustrating plaque formation in the Dbtg mice (brown) ac-
companied by astrocytosis (black). (B) Pooled data showing levels of
Aβ(40) and Aβ(42) in Wt and DbTg mice.
Fitzjohn et al. Molecular Brain 2010, 3:21
Page 4 of 9
± 0.01 and 0.004 ± 0.003 nmol/g wet weight tissue in Wt
mice (Fig. 1B). In addition, compared to the single trans-
genic APP695SWE mouse, the Aβ(42)/Aβ(40) ratio is
enhanced throughout the life of the animal [14,26].
Plaques were also evident in aged DbTg mice throughout
the hippocampus, but were not evident in Wt animals
(Fig. 1A; ).
Basal synaptic transmission
Synaptic transmission was quantified over a wide range of
stimulus intensities and was analysed in terms of fEPSP
slope versus stimulus intensity (Fig. 2) and fEPSP slope
versus fibre volley (FV) amplitude (Fig. 3). Using both
methods of analysis there was a pronounced, age-depen-
dent decline in synaptic transmission in slices obtained
from both Wt and DbTg mice of between 2 and 9 months
of age. Indeed, it was difficult to obtain viable synaptic
responses from slices prepared form both Wt and DbTg
animals in the 9 month age group and many failed to pro-
duce a fEPSP. For this reason we performed the dissec-
tions for the 14 month age group in the presence of
kynurenic acid, since this treatment has been shown to
greatly improve slice viability of some transgenic mouse
strains [12,14]. This treatment resulted in considerably
improved synaptic viability (Figs 2 &3).
The input-output curves were generally similar for both
genotypes, at all ages studied (Figs 2 &3). For example, in
14 month old mice the slope of the relationship between
fEPSP slope and FV amplitude was 2.34 ± 0.25 V.s-1.mV-1
[47 (11)] in Wt animals and 2.42 ± 0.31 V.s-1.mV-1 [43
(13)] in DbTg mice (p > 0.05). The maximum obtained
fEPSPs were also similar in the two groups. For example,
in 14 month old mice the fEPSP evoked by 45 V stimula-
tion was 2.32 ± 0.21 V.s-1 [47 (11)] and 2.21 ± 0.22 V.s-1 [43
(13)] (p > 0.05) in Wt and DbTg mice, respectively.
In all age groups, there was no difference in the level of
PPF (slope of second response/slope of first response)
between DbTg and Wt mice. For example, at an inter-
stimulus interval (ISI) of 50 ms the PPF ratios for Wt and
DbTg mice were, respectively, at 2 months: 1.86 ± 0.05 [30
Figure 2 Age-dependent reduction in synaptic transmission in
CA1 region of Wt and DbTg mice. (A) Individual examples of fEPSPs
recorded with a stimulus intensity of 10, 20 and 30 V from slices pre-
pared from 14 month old Wt and DbTg mice. Scale bar 0.5 mV, 10 ms.
Stimuli were delivered at the times indicated by the arrows and stimu-
lus artefacts have been removed for clarity. (B - D) Pooled data showing
relationship between fEPSP slope and stimulus intensity at 2, 6, 9 and
14 months. In this and following figures symbols are [black circle] for
Wt and [white circle] for DbTg results.
Figure 3 Analysis of fibre volley (FV) amplitude and fEPSP slope.
Pooled data from 2, 6, 9 and 14 month old Wt and DbTg animals re-
spectively grouped by stimulus intensity ([black circle] Wt, [white cir-
Fitzjohn et al. Molecular Brain 2010, 3:21
Page 5 of 9
(13)] and 1.99 ± 0.13 [20 (10)]; 6 months: 1.93 ± 0.07 [24
(8)] and 1.80 ± 0.15 [15 (7)]; 9 months: 1.81 ± 0.10 [28
(10)] and 1.75 ± 0.09 [19 (8)] and 14 months: 1.72 ± 0.03
[28 (8)] and 1.77 ± 0.04 [24 (6)] (in all cases, p > 0.05).
There was also no age-related change in the level of PPF
in either Wt or DbTg animals (p > 0.05 at all stimulus
intervals used). PPF data over a range of inter-pulse inter-
vals for the 2 and 14 month age group are presented in
A theta burst stimulus (total of 40 stimuli) induced robust
LTP in the CA1 region in all age groups. The level of LTP
was similar in both genotypes across all ages, quantified
for up to 60 min following theta burst stimulation (Fig.
5A-D; p > 0.05 at all age groups). For example, the level of
LTP observed 60 minutes after theta burst stimulation in
Wt and DbTg animals was, at 2 months: 156 ± 9% [9 (5)]
and 171 ± 12% [8 (6)]; 6 months: 205 ± 17% [18 (9)] and
216 ± 32% [13 (7)]; 9 months: 171 ± 9 [15 (8)] and 211 ±
22% [8 (4)]; 14 months: 186 ± 10% [23 (13)] and 178 ±
15% [16 (9)]. There was no age-related change in the level
of LTP seen following theta burst stimulation for either
Wt of DbTg mice. In the 14 month age group, a subset of
slices was followed for over 3 h following theta burst
stimulation. There was no difference between genotypes,
the level of LTP seen 3.5 hours post-theta burst stimula-
tion in Wt and DbTg animals was 196 ± 28% [9 (5)] and
183 ± 20% [9 (5)] (p > 0.05; Fig. 5E).
In a second series of experiments, a stronger induction
protocol was delivered (total of 400 stimuli) and LTP
again followed for over 3 h (Fig. 6). The levels of LTP were
similar for each genotype at all ages (p > 0.05 at 3.5 h),
thus at 3.5 hours post-LTP induction the level of LTP in
Wt and DbTg animals was, at 2 months: 189 ± 18% [10
(5)] and 188 ± 28 [7 (3)]; 6 months 151 ± 17% [11 (9)] and
139 ± 23% [8 (5)]; 9 months: 177 ± 26% [11 (6)] and 159 ±
23% [9 (5)]; 14 months: 203 ± 12% [20 (9)] and 168 ± 14%
[16 (8)]. Again, there was no age-related change in the
level of LTP induced by this strong induction protocol for
either Wt or DbTg animals.
In DbTg mice over-expressing the human familial AD
transgenes APP695SWE and PS1A246E, Aβ peptides accu-
mulate in an accelerated age-dependent manner with an
early enhancement of the Aβ(42)/Aβ(40) ratio (see also
). Accelerated production of Aβ has also been
reported in different mouse strains expressing double
mutations of APP and PS1 (reviewed in ). However,
Figure 4 PPF is normal in DbTg mice. (A) Example traces taken from
14 month old Wt (black circle) and DbTg (white circle) animals show-
ing PPF at ISIs of 25 and 100 ms. Scale bar 0.5 mV, 20 ms. (B, C) Pooled
data for 2 (B) and 14 (C) month-old animals.
Figure 5 LTP induced by a theta burst stimulus is normal in DbTg
mice. (A) Example experiment taken from 14 month old Wt slice. LTP
was induced at the time indicated by the arrowhead. Example traces
are taken from the time points immediately prior to and 60 min after
the induction of LTP. Scale bar 0.5 mV, 20 ms. (B) Example experiment
taken from 14 month old DbTg slice. (C) Pooled data for 2 month-old
animals ([black circle] Wt, [white circle] DbTg). In this and subsequent
figures showing pooled data, data points are shown at two minute in-
tervals. (D) Summary of LTP as a percentage of baseline at 60 min post-
tetanus for the different age groups. (E) Pooled data from a subset of
slices from 14 month old animals where LTP was followed for 3.5 h af-
ter the theta burst. Scale bar 0.5 mV, 10 ms.
Fitzjohn et al. Molecular Brain 2010, 3:21
Page 6 of 9
there has been little work carried out into studying syn-
aptic function and plasticity in these multiple transgenic
mice lines. We find that normal LTP in the CA1 region
can be recorded over a wide age range and that there is
little, if any, difference between the DbTg and the Wt
Effects on basal synaptic transmission
Consistent with our earlier report on the APP695SWE sin-
gle transgenic mouse  we found that there was an age-
dependent reduction in fEPSPs evoked by a fixed stimu-
lus intensity over a wide range. The deficit was clearly
present when synaptic transmission was compared with
the amplitude of the presynaptic fibre volley and there-
fore reflects a reduction in the input-output relationship.
This age-related decrease in basal synaptic transmission
was similar in both Wt and DbTg mice, with little if any
difference between the two groups at each age point.
Similarly, Volianskis et al.  recently reported a similar
age-related decrease in basal transmission in mice over-
expressing APP695SWE and PS1ΔE9 transgenes, which was
similar in both groups of animals. Consistent with previ-
ous studies [12,14], the reduction in synaptic transmis-
sion was prevented by blockade of ionotropic glutamate
receptors with kynurenic acid during slice preparation,
suggesting that it was due to increased susceptibility to
excitotoxicity, which may be a characteristic of the back-
ground mouse strain on which the transgenes are
expressed. Interestingly, hippocampal cultures prepared
from double transgenic animals (APPSWE and PS1L166P)
show a reduction in excitatory synapses compared to cul-
tures from wildtype or APPSWE mice, suggesting that the
inclusion of the PS1 transgene may have an additional
effect on glutamatergic synapse formation under some
Here we have shown that, even at 14 month of age,
there is no deficit in basal transmission in DbTg com-
pared to Wt animals. This is despite the fact that Aβ lev-
els are greatly enhanced in these animals and plaques are
also evident in the hippocampus and other brain regions
(see ). Thus it appears that the increased production
of Aβ in these mice does not impair basal synaptic func-
Effects on LTP
Previous studies using transgenic mouse modes of
Alzheimer's disease have resulted in little consensus on
the effects of mutations in APP and PS1 with respect to
LTP. For example, a reduction of LTP has been reported
in mice that over-express either the London (V642I; 
or Swedish (APP695SWE; [12,29] mutations in APP. In
contrast, no impairment was observed in single trans-
genic mice that over-express the V717F mutant form of
APP (APPInd; [30-32]) and in studies using the
APP695SWE mutation [14,15]. Both the ΔE9  and
A246E  mutations in PS1 have previously been shown
to lead to enhanced LTP expression. Mice under-express-
ing PS1 have displayed reduced levels of LTP in one study
 but normal LTP in another .
Few studies to date have been conducted using mice
expressing double mutations in APP and PS1. One previ-
ous study reported an increased rate of decay in dentate
gyrus LTP in vivo in 17-18 month old mice expressing the
APP695SWE and PS1A246E, mutations , but normal
CA1 LTP in vitro at this age. Two studies have found
impairments in hippocampal LTP  and hippocampal-
dependent learning [37,38] in both aged wildtype and
transgenic mice overexpressing mutated APP and PS1,
suggesting that deficits were independent of Aβ or plaque
load. Although impairments in CA1 LTP have been
observed in mice expressing mutations in both APP and
PS1 in some studies , , a recent study using mice
expressing both APP695SWE and PS1ΔE9 found no deficit
in hippocampal LTP in vitro at all ages studied (up to 12
months of age;). In our study we were unable to
detect any changes in LTP at CA1 synapses using two
induction protocols (that employed respectively 40 and
400 stimuli). Of course, we cannot exclude the possibility
Figure 6 LTP induced by repeated tetani is normal in DbTg mice.
(A-C) Pooled data for slices from 2, 6 and 9 month old animals ([black
circle] Wt, [white circle] DbTg). (D) Summary of the LTP as a percentage
of baseline at 3.5 hours after the last tetanus for the different age
groups. (E) Pooled data for slices from 14 month old animals. Traces are
taken from the time points immediately prior to induction of LTP and
3.5 h after the last tetanus. Scale bar 0.5 mV, 5 ms. LTP was induced by
the delivery of four tetanic stimuli separated by 5 min at the times in-
dicated by the arrowheads.
Fitzjohn et al. Molecular Brain 2010, 3:21
Page 7 of 9
that alterations in LTP may be observed with other pat-
terns of activation or under different experimental condi-
tions or in other pathways. Interestingly, a recent study
has shown that deficits in LTP in vitro in mice overex-
pressing the Swedish mutant of APP are only seen if the
animals are previously exposed to spatial training, not in
naïve animals , suggesting that deficits in plasticity
are subtle and subject to alterations based on prior expe-
rience. The primary conclusion, however, is that LTP is
readily induced despite the pronounced and long-lasting
increase in Aβ(42) and Aβ(40) levels in the hippocampus.
Alzheimer's disease is characterised by synaptic degen-
eration and changes in dendritic and axonal morphology
[41-43]. Whilst these processes are not important for the
earliest phase of LTP, they may become more important
in the protein synthesis dependent phase of LTP. For this
reason we extended our analysis of LTP beyond that
which has been studied previously in slices obtained from
transgenic models of Alzheimer's disease. However, we
noticed little difference in LTP between the genotypes,
even when followed for over 3 h post-induction. Theta
patterns of activity are more physiological than tetanic
stimulation and involve the activation of presynaptic
GABAB receptors to transiently suppress GABA inhibi-
tion and thereby facilitate the activation of NMDA recep-
tors . Thus, LTP induced by theta patterns of activity
may be more susceptible to regulatory influences, in par-
ticular those that affect GABA-mediated inhibition. In
this context, we have previously observed that a deficit in
LTP observed in APP null nice is normalised when
GABAA receptor-mediated inhibition is blocked .
The finding that both basal synaptic transmission and
LTP is normal in region CA1 of the hippocampus even
when Aβ levels are greatly enhanced and plaques are
present may be considered somewhat surprising, particu-
larly as the presence of plaques would be expected to dis-
rupt the neuronal organisation of this region. However,
these findings are consistent with some of the previous
studies utilising transgenic mice relevant to AD. This
would suggest that synaptic physiology remains normal
in situations where Aβ levels are elevated, at least in the
CA1 region of the hippocampus. However, our experi-
ments were performed without visualisation of plaques in
the slices and thus we cannot rule out the possibility that
the majority of our recording sites were in areas not con-
taining plaques and that recording from regions neigh-
bouring plaques may reveal a deficit in basal synaptic
transmission and/or plasticity. This may also account for
discrepancies between studies of transgenic mice
expressing AD related proteins. Thus further experi-
ments could target recordings from plaque containing
regions. Ours and other studies investigating synaptic
physiology from acutely prepared brain slices give an
indication of transmission at individual or sets of syn-
apses but do not provide information on the function of
the hippocampus as a whole. If transmission and/or plas-
ticity are impaired at only a fraction of the neurones in
this structure then function (e.g. spatial learning) may be
Increasing evidence suggests that the form in which Aβ
is present in the brain is crucial in terms of whether neu-
ronal function and memory is impaired. Thus oligomers
rather than monomers or fibrils of Aβ induce synapse loss
and impair memory [46-48]. Aβ exists in the AD brain as
a polydisperse mixture of high order oligomers and only
these high molecular weight oligomers bind to hip-
pocampal neurons . Furthermore, cerebral injection
of cell medium containing oligomers and monomers, but
not fibrils, inhibits LTP in vivo . As such the existence
of Aβ oligomers rather then plaques may cause neuronal
damage, and there is little correlation between the pres-
ence of plaques and severity of dementia in humans .
It may be, therefore, that although the mice used in the
current study display Aβ plaques, they do not produce an
oligomeric form of Aβ that is detrimental to neuronal
health and function. Alternatively, it may be that a loss of
normal APP function rather than an increase in Aβ may
cause an impairment in LTP, as APP knockout mice show
deficits in LTP , and so differences in secreted APP
between transgenic strains, which can have trophic and
neuroprotective effects , may lead to differences in
synaptic transmission and plasticity.
Another possibility for our finding, a lack of effect on
LTP in the DbTg mice, is that other factors may be
required for generating AD-related impairments in hip-
pocampal function, for example altered tau . Consis-
tent with this Roberson and colleagues have shown that
reducing tau expression can affect amyloid related toxic-
ity in transgenic mice without altering plaque deposition
. Human patients have additional pathology relative
to transgenic mouse models utilising mutations in APP
and PS1. In particular, although the mice show Aβ
plaques, they do not display intracellular tangles of
hyperphosphorylated tau protein . Oddo and col-
leagues  generated a triple transgenic mouse express-
ing mutated APP (APPSWE), PS1 (M146V mutation) and
tau (P301L mutation), which showed progressive devel-
opment of both plaques and tangles as well as a reduction
in hippocampal LTP. Such mice may represent a more
robust model of AD.
In conclusion, it is clear from our present experiments
that the cellular machinery for induction and expression
of LTP at CA1 synapses is intact in these DbTg mice. This
is apparent even in aged mice, which have been exposed
to greatly elevated levels of Aβ peptides for over 6
Fitzjohn et al. Molecular Brain 2010, 3:21
Page 8 of 9
Frederick Kuenzi, Thomas Rosahl, David Smith, Huw Lewis and Guy Seabrook
were employees of Merck Research Laboratories when this work was carried
out. There are no other conflicts of interest.
Conceived and designed the experiments: SMF, FK, RAM, TWR, GRS, GLC
Performed the experiments: FK, RAM, HL, DS, GRS
Analyzed the data: SMF, FK, RAM, GRS
Wrote the paper: SMF, FK, RAM, GRS, GLC.
We wish to thank David S. Reynolds for assistance in this project. The work was
supported by a Medical Research Council (MRC) LINK award G9710681. The
MRC was not involved in the design and conduct of the study, in the collec-
tion, analysis, and interpretation of the data, and in the preparation, review, or
approval of the manuscript.
1MRC Centre for Synaptic Plasticity, Department of Anatomy, University of
Bristol, University Walk, Bristol, BS8 1TD, UK, 2The Neuroscience Research
Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick
Road, Harlow, Essex, CM20 2QR, UK, 3Merck Research Laboratories, 126 E.
Lincoln Ave, Rahway, NJ 07065, USA and 4Eli Lilly & Company, Lilly Corporate
Center, Indianapolis, Indiana 46285, USA
1.Hardy J: Amyloid, the presenilins and Alzheimer's disease. Trends
Neurosci 1997, 20(4):154-159.
2. Price DL, Sisodia SS: Mutant genes in familial Alzheimer's disease and
transgenic models. Annu Rev Neurosci 1998, 21:479-505.
3. Newman M, Musgrave IF, Lardelli M: Alzheimer disease:
amyloidogenesis, the presenilins and animal models. Biochimica et
biophysica acta 2007, 1772(3):285-297.
4.Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, Seubert P, Vigo-
Pelfrey C, Lieberburg I, Selkoe DJ: Mutation of the beta-amyloid
precursor protein in familial Alzheimer's disease increases beta-protein
production. Nature 1992, 360(6405):672-674.
5. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H,
Lin C, Li G, Holman K, et al.: Cloning of a gene bearing missense
mutations in early-onset familial Alzheimer's disease. Nature 1995,
6. Fraser PE, Yang DS, Yu G, Levesque L, Nishimura M, Arawaka S, Serpell LC,
Rogaeva E, St George-Hyslop P: Presenilin structure, function and role in
Alzheimer disease. Biochimica et biophysica acta 2000, 1502(1):1-15.
7.Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, Johnson-
Wood K, Lee M, Seubert P, Davis A, et al.: Mutant presenilins of
Alzheimer's disease increase production of 42-residue amyloid beta-
protein in both transfected cells and transgenic mice. Nature medicine
8.Zhang Z, Nadeau P, Song W, Donoviel D, Yuan M, Bernstein A, Yankner BA:
Presenilins are required for gamma-secretase cleavage of beta-APP
and transmembrane cleavage of Notch-1. Nat Cell Biol 2000,
9.Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F,
Cole G: Correlative memory deficits, Abeta elevation, and amyloid
plaques in transgenic mice. Science (New York, NY) 1996,
10. Irizarry MC, McNamara M, Fedorchak K, Hsiao K, Hyman BT: APPSw
transgenic mice develop age-related A beta deposits and neuropil
abnormalities, but no neuronal loss in CA1. JNeuropatholExpNeurol
11. Frautschy SA, Yang F, Irrizarry M, Hyman B, Saido TC, Hsiao K, Cole GM:
Microglial response to amyloid plaques in APPsw transgenic mice. Am
J Pathol 1998, 152(1):307-317.
12. Chapman PF, White GL, Jones MW, Cooper-Blacketer D, Marshall VJ,
Irizarry M, Younkin L, Good MA, Bliss TV, Hyman BT, et al.: Impaired
synaptic plasticity and learning in aged amyloid precursor protein
transgenic mice. Nature neuroscience 1999, 2(3):271-276.
13. Fitzjohn SM, Doherty AJ, Collingridge GL: The use of the hippocampal
slice preparation in the study of Alzheimer's disease. European journal
of pharmacology 2008, 585:50-59.
14. Fitzjohn SM, Morton RA, Kuenzi F, Rosahl TW, Shearman M, Lewis H, Smith
D, Reynolds DS, Davies CH, Collingridge GL, et al.: Age-related
impairment of synaptic transmission but normal long-term
potentiation in transgenic mice that overexpress the human
APP695SWE mutant form of amyloid precursor protein. Journal of
Neuroscience 2001, 21(13):4691-4698.
15. Brown JT, Richardson JC, Collingridge GL, Randall AD, Davies CH: Synaptic
transmission and synchronous activity is disrupted in hippocampal
slices taken from aged TAS10 mice. Hippocampus 2005, 15(1):110-117.
16. Parent A, Linden DJ, Sisodia SS, Borchelt DR: Synaptic transmission and
hippocampal long-term potentiation in transgenic mice expressing
FAD-linked presenilin 1. NeurobiolDis 1999, 6(1):56-62.
17. Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T,
Prada CM, Kim G, Seekins S, Yager D, et al.: Familial Alzheimer's disease-
linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in
vivo. Neuron 1996, 17(5):1005-1013.
18. Duyckaerts C, Potier MC, Delatour B: Alzheimer disease models and
human neuropathology: similarities and differences. Acta Neuropathol
19. Trinchese F, Liu S, Battaglia F, Walter S, Mathews PM, Arancio O:
Progressive age-related development of Alzheimer-like pathology in
APP/PS1 mice. Annals of neurology 2004, 55(6):801-814.
20. Chang EH, Savage MJ, Flood DG, Thomas JM, Levy RB, Mahadomrongkul
V, Shirao T, Aoki C, Huerta PT: AMPA receptor downscaling at the onset
of Alzheimer's disease pathology in double knockin mice. Proceedings
of the National Academy of Sciences of the United States of America 2006,
21. Volianskis A, Kostner R, Molgaard M, Hass S, Jensen MS: Episodic memory
deficits are not related to altered glutamatergic synaptic transmission
and plasticity in the CA1 hippocampus of the APPswe/PS1DeltaE9-
deleted transgenic mice model of beta-amyloidosis. Neurobiology of
aging 2010, 31:1173-1187.
22. Hsiao KK, Borchelt DR, Olson K, Johannsdottir R, Kitt C, Yunis W, Xu S,
Eckman C, Younkin S, Price D, et al.: Age-related CNS disorder and early
death in transgenic FVB/N mice overexpressing Alzheimer amyloid
precursor proteins. Neuron 1995, 15(5):1203-1218.
23. Qian S, Jiang P, Guan XM, Singh G, Trumbauer ME, Yu H, Chen HY, Van de
Ploeg LH, Zheng H: Mutant human presenilin 1 protects presenilin 1
null mouse against embryonic lethality and elevates Abeta1-42/43
expression. Neuron 1998, 20(3):611-617.
24. Kuenzi F, Rosahl TW, Morton RA, Fitzjohn SM, Collingridge GL, Seabrook
GR: Hippocampal synaptic plasticity in mice carrying the rd mutation
in the gene encoding cGMP phosphodiesterase type 6 (PDE6). Brain
Res 2003, 967(1-2):144-151.
25. Wimer RE, Wimer CC, Alameddine L, Cohen AJ: The mouse gene retinal
degeneration (rd) may reduce the number of neurons present in the
adult hippocampal dentate gyrus. Brain research 1991, 547(2):275-278.
26. Lewis HD, Beher D, Smith D, Hewson L, Cookson N, Reynolds DS, Dawson
GR, Jiang M, Van der Ploeg LH, Qian S, et al.: Novel aspects of
accumulation dynamics and A beta composition in transgenic models
of AD. Neurobiology of aging 2004, 25(9):1175-1185.
27. Priller C, Mitteregger G, Paluch S, Vassallo N, Staufenbiel M, Kretzschmar
HA, Jucker M, Herms J: Excitatory synaptic transmission is depressed in
cultured hippocampal neurons of APP/PS1 mice. Neurobiology of aging
28. Moechars D, Dewachter I, Lorent K, Reverse D, Baekelandt V, Naidu A,
Tesseur I, Spittaels K, Haute CV, Checler F, et al.: Early phenotypic changes
in transgenic mice that overexpress different mutants of amyloid
precursor protein in brain. JBiolChem 1999, 274(10):6483-6492.
29. Jacobsen JS, Wu CC, Redwine JM, Comery TA, Arias R, Bowlby M, Martone
R, Morrison JH, Pangalos MN, Reinhart PH, et al.: Early-onset behavioral
and synaptic deficits in a mouse model of Alzheimer's disease.
Proceedings of the National Academy of Sciences of the United States of
America 2006, 103(13):5161-5166.
30. Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C,
Carr T, Clemens J, Donaldson T, Gillespie F: Alzheimer-type
Received: 8 June 2010 Accepted: 14 July 2010
Published: 14 July 2010
This article is available from: http://www.molecularbrain.com/content/3/1/21 © 2010 Fitzjohn et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Molecular Brain 2010, 3:21
Fitzjohn et al. Molecular Brain 2010, 3:21
Page 9 of 9
neuropathology in transgenic mice overexpressing V717F beta-
amyloid precursor protein. Nature 1995, 373(6514):523-527.
31. Hsia AY, Masliah E, McConlogue L, Yu GQ, Tatsuno G, Hu K, Kholodenko D,
Malenka RC, Nicoll RA, Mucke L: Plaque-independent disruption of
neural circuits in Alzheimer's disease mouse models.
ProcNatlAcadSciUSA 1999, 96(6):3228-3233.
32. Larson J, Lynch G, Games D, Seubert P: Alterations in synaptic
transmission and long-term potentiation in hippocampal slices from
young and aged PDAPP mice. Brain Res 1999, 840(1-2):23-35.
33. Zaman SH, Parent A, Laskey A, Lee MK, Borchelt DR, Sisodia SS, Malinow R:
Enhanced synaptic potentiation in transgenic mice expressing
presenilin 1 familial Alzheimer's disease mutation is normalized with a
benzodiazepine. NeurobiolDis 2000, 7(1):54-63.
34. Morton RA, Kuenzi FM, Fitzjohn SM, Rosahl TW, Smith D, Zheng H,
Shearman M, Collingridge GL, Seabrook GR: Impairment in hippocampal
long-term potentiation in mice under-expressing the Alzheimer's
disease related gene presenilin-1. NeurosciLett 2002, 319(1):37-40.
35. Yu H, Saura CA, Choi SY, Sun LD, Yang X, Handler M, Kawarabayashi T,
Younkin L, Fedeles B, Wilson MA, et al.: APP processing and synaptic
plasticity in presenilin-1 conditional knockout mice. Neuron 2001,
36. Gureviciene I, Ikonen S, Gurevicius K, Sarkaki A, van Groen T, Pussinen R,
Ylinen A, Tanila H: Normal induction but accelerated decay of LTP in APP
+ PS1 transgenic mice. Neurobiology of disease 2004, 15(2):188-195.
37. Gruart A, Lopez-Ramos JC, Munoz MD, Delgado-Garcia JM: Aged wild-
type and APP, PS1, and APP + PS1 mice present similar deficits in
associative learning and synaptic plasticity independent of amyloid
load. Neurobiology of disease 2008, 30(3):439-450.
38. Park SW, Ko HG, Lee N, Lee HR, Rim YS, Kim H, Lee K, Kaang BK: Aged wild-
type littermates and APPswe+PS1/ΔE9 mice present similar deficits in
associative learning and spatial memory independent of amyloid load.
Genes & Genomics 2010, 32:63-70.
39. Gengler S, Hamilton A, Holscher C: Synaptic plasticity in the
hippocampus of a APP/PS1 mouse model of Alzheimer's disease is
impaired in old but not young mice. PLoS ONE 5(3):e9764.
40. Middei S, Roberto A, Berretta N, Panico MB, Lista S, Bernardi G, Mercuri NB,
Ammassari-Teule M, Nistico R: Learning discloses abnormal structural
and functional plasticity at hippocampal synapses in the APP23 mouse
model of Alzheimer's disease. Learning & memory (Cold Spring Harbor, NY
41. Knowles RB, Wyart C, Buldyrev SV, Cruz L, Urbanc B, Hasselmo ME, Stanley
HE, Hyman BT: Plaque-induced neurite abnormalities: implications for
disruption of neural networks in Alzheimer's disease. Proceedings of the
National Academy of Sciences of the United States of America 1999,
42. Phinney AL, Deller T, Stalder M, Calhoun ME, Frotscher M, Sommer B,
Staufenbiel M, Jucker M: Cerebral amyloid induces aberrant axonal
sprouting and ectopic terminal formation in amyloid precursor protein
transgenic mice. J Neurosci 1999, 19(19):8552-8559.
43. Arendt T: Alzheimer's disease as a disorder of mechanisms underlying
structural brain self-organization. Neuroscience 2001, 102(4):723-765.
44. Davies CH, Collingridge GL: The physiological regulation of synaptic
inhibition by GABAB autoreceptors in rat hippocampus. Journal of
Physiology 1993, 472:245-265.
45. Fitzjohn SM, Morton RA, Kuenzi F, Davies CH, Seabrook GR, Collingridge
GL: Similar levels of long-term potentiation in amyloid precursor
protein -null and wild-type mice in the CA1 region of picrotoxin
treated slices. Neuroscience letters 2000, 288(1):9-12.
46. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ,
Selkoe DJ: Naturally secreted oligomers of amyloid beta protein
potently inhibit hippocampal long-term potentiation in vivo. Nature
47. Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe
KH: A specific amyloid-beta protein assembly in the brain impairs
memory. Nature 2006, 440(7082):352-357.
48. Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini
BL: Natural oligomers of the Alzheimer amyloid-beta protein induce
reversible synapse loss by modulating an NMDA-type glutamate
receptor-dependent signaling pathway. J Neurosci 2007,
49. Hepler RW, Grimm KM, Nahas DD, Breese R, Dodson EC, Acton P, Keller
PM, Yeager M, Wang H, Shughrue P, et al.: Solution state characterization
of amyloid beta-derived diffusible ligands. Biochemistry 2006,
50. Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA,
Katzman R: Physical basis of cognitive alterations in Alzheimer's
disease: synapse loss is the major correlate of cognitive impairment.
Annals of neurology 1991, 30(4):572-580.
51. Goodman Y, Mattson MP: Secreted forms of beta-amyloid precursor
protein protect hippocampal neurons against amyloid beta-peptide-
induced oxidative injury. Experimental neurology 1994, 128(1):1-12.
52. Seabrook GR, Ray WJ, Shearman M, Hutton M: Beyond amyloid: the next
generation of Alzheimer's disease therapeutics. Mol Interv 2007,
53. Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, Gerstein H,
Yu GQ, Mucke L: Reducing endogenous tau ameliorates amyloid beta-
induced deficits in an Alzheimer's disease mouse model. Science (New
York, NY) 2007, 316(5825):750-754.
54. Ashe KH: Mechanisms of memory loss in Abeta and tau mouse models.
Biochem Soc Trans 2005, 33(Pt 4):591-594.
55. Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R,
Metherate R, Mattson MP, Akbari Y, LaFerla FM: Triple-transgenic model
of Alzheimer's disease with plaques and tangles: intracellular Abeta
and synaptic dysfunction. Neuron 2003, 39(3):409-421.
Cite this article as: Fitzjohn et al., A study of long-term potentiation in trans-
genic mice over-expressing mutant forms of both amyloid precursor protein
and presenilin-1 Molecular Brain 2010, 3:21