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INTRODUCTION
In AD,
soluble oligomers of amyloid β (Aβ) are believed to be one of the major causes
of synaptic degeneration and cognitive dysfunction in patients in the early
stages of AD [1]. This hypothesis is based primarily on experimental studies
demonstrating that Aβ oligomers impair normal synaptic plasticity [2] and
memory [2,3] and cause loss of synapses when applied exogenously to rat
cerebral ventricle, cultured brain slices, or dissociated neurons[4]. Moreover,
several studies have previously supported this evidence by demonstrating a
direct correlation between levels of soluble oligomers of Aβ and synaptic and
cognitive impairment in humans [5] as well as animalmodels of AD[6]. AD is a
heterogeneous and complex disorder in which hundreds of genes distributed
across the human genome might be involved in close cooperation with
environmental factors and epigenetic phenomena, leading to the
neurodegeneration process that characterizes this disease [7-12]. In patients,
the clinical detection of amyloid plaques is currently based on positron
emission tomography (PET) imaging with three radioactive agents recently
approved by the Food and Drug Administration (FDA)[13]. However, PET presents a
low spatial resolution that inhibits the visualization of individual plaques,
while in animal models; PET studies have provided controversial results [14].
In particular, some studies successfully detected amyloid progression in APP23
[15] and 5xFAD [16] mice while other studies failed to detect these amyloidotic
changes [17,18]. Other imaging technologies have also been developed to detect
amyloid plaques in animals, such as optical or two-photon imaging. Although the
Two-photon imaging can detect individual amyloid plaques at very high
resolution (1 μm), its limitation is the impossibility of recording large
images of the whole brain [19].
In the past decades, the gene-targeted technology applied to generate
specific transgenic mice has proven to be crucial for modeling the main
hallmarks of AD neuropathology, although no mouse model fully recapitulates its
entire neuropathological spectrum [20]. At the present time, numerous models
have successfully replicated amyloid plaque deposition, generally by inducing
high levels of APP overexpression. Moreover, the inclusion of a mutant PS1
allele can increase the deposition rate of this amyloid plaque deposition as
well as exacerbating its severity [21]. However, the majority of AD models have
developed one hallmark pathological lesion that has been insufficient to
trigger the development of the other signature lesion. Consequently, to develop
the manifestation of both plaques and tangles in the same model has required
the introduction of multiple transgenes into the same mouse, which has
generally been achieved by crossing several independent transgenic lines, or
alternatively, by microinjecting pathological protein into the brains of
single-transgenic mice [22,23].
Here we describe the comparative development of the main AD hallmark in
a novel triple-transgenic model (APP/BIN1/COPS5) and double-transgenic model
(APP/PS1). We report that (to our knowledge) this is the first comparative
profile between these two robust transgenic models in AD-affected brain
regions. The 3×Tg-AD mice develop extracellular Aβ deposits prior to those
observed in 2xTg-AD mice, consistent with the amyloid cascade hypothesis.
Although both mice exhibited deficits in synaptic plasticity, the severity of
the neuropathological degeneration is more severe and earlier in onset in the
3×Tg-AD mice. This study will be useful for addressing the impact of 3×Tg-AD
mice as a new powerful AD model by recapitulating the early-onset
neurodegenerative effects of Aβ deposits.
MATERIALS AND
METHODS
Mouse models
The double-transgenic mice B6C3F1/J (APPswe/PS1dE9), expressing a
chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant
human presenilin 1 (PS1-ΔE9), both directed toward central nervous system (CNS)
neurons, exhibit Aβ plaques in the hippocampus andcortex beginning at 6months
of age (Jackson Laboratory, Bar Harbor, ME).
The triple-transgenic 3xTg-AD mice (APP/BIN1/COPS5), which overexpress
the Swedish mutation of APP (human amyloid precursor protein) together with
BIN1 (bridging integrator 1, AMPH2) and COPS5 (COP9 constitutive
photomorphogenic homolog subunit 5, Jab1), individually generated in Dr.
Lakshmana´s lab and backcross-bred in our laboratory, closely mimicthe human
brain pathology. DNA constructs and transgenic generation proceedings have been
described previously [24,25] and were sequence-verified prior to breeding the
transgenic colony. All experimental procedures were performed in accordance
with the guidelines established by the European Communities Council Directive
(86/609/EEC), EU Directive 2010/63/EU, and Spanish Royal Decree 1201/2005 on
animal experimentation,and were approved by the Ethics Committee of the
EuroEspes Biotechnology Research Centre (Permit number: EE/2015-184).
Experiment Design
Double- (APP/PS1) and triple- (BIN1/COPS5/APP) transgenic mice of 0-1,
6, and 12 months of age were used during experimentation and then sacrificed,
together with wild-type mice used as control groups. Double- and
triple-transgenic mice were randomly divided into these 5 experimental groups
by age (Figure 1), as follows: Group
A (0-1 months of age) was formed by 15 mice (12 transgenic and 3 wild-type
mice); group B (6 months of age), formed by 15 mice (12 transgenic and 3
wild-type mice); and group C (12 months of age), formed by 9 mice (6 transgenic
and 3 wild-type mice).
Immunohistochemistry
Immunohistochemical Aβ hallmarks were analyzed by using the methods described,
exactly as previously published [26-29]. In summary, parallel transverse
sections (12-14 µm) from the left half of the brain were obtained by cryostat
and pretreated with H2O2 in phosphate-buffered saline at
room temperature for 15 minutes, to eliminate endogenous peroxidase. They were
then rinsed twice in 0.05M Trizma buffered saline (TBS) containing 0.1%
Tween-20 at pH 7.4 (TBS-T) for 10 minutes each, pretreated with blocking
avidin/biotin kit (Vector) and then incubated overnight with the primary
antibodies (Millipore; 1/1000). The sections were successively rinsed in TBS-T,
incubated in goat IgG anti-rat (Millipore) or goat IgG anti-mouse (Sigma),
depending on the primary antibody, for 1 hour, rinsed in TBS-T, and then
incubated for 30 minutes in ABC kit system (Vectastain; Vector). The labeling
was revealed by incubating sections with 3,3-diaminobenzidine (Sigma) with
chromogen and hydrogen peroxide as oxidant. In several adjacent sections,
negative controls performed by omitting the primary, secondary, or tertiary
antibodies showed no immunostaining. Images were visualized using a microscope
(Olympus BX50) and digitized using a digital camera (DP-10; Olympus). The
photomicrographs were adjusted for brightness and contrast with Corel Photo-Paint
(Corel 11, Ottawa, Canada) and figure images were composed using Corel Draw.
RESULTS
Histopathological
comparison of Aβ deposits in AD transgenic mice
Immunohistochemical data obtained from mouse brain analysis at 0-1, 6,
and 12 months of age showed that APP, Bin1 and COPS5 expressing genes promote
the severity of Aβ plaque deposits throughout the first age of development (Figure 1A-F). Results indicated that,
when compared with double-(APP/PS1) transgenic mice, the triple-transgenic mice
(APP/Bin1/COPS5) showed Aβ deposits at very early stages of development (0-1
month of age). Results also showed that the plaque burden density observed in
affected brain regions of triple-transgenic mice was notably increased,
compared with double-transgenic mice of the same age (Figure 1A-F). As shown in figure
1, all the triple-transgenic mice showed a progressive accumulation of Aβ
deposits in the brain, while in APP/PS1 Tg mice, cerebral Aβ plaques were only
observed at 6 months of age.
Aβ plaques in transgenic models of 0-1 months of age
Aβ immunoreactive plaques were first detectable in neocortical regions
and subsequently in CA1 pyramidal neurons in newborn triple-transgenic
micebetween 0-1 month of age. Aβ deposits first became apparent in the
hippocampus (Figure 1A) and were
consistently evident by the end of the first month. Also, by this point in
time, Aβ deposits were apparent in the frontal cortex, suggesting that there is
an age-related and regional brain correlation to Aβ deposition in these 3×Tg-AD
mice. A detailed examination of the brain tissues at higher magnification
showed that, over the course of 0-1 months, the 3×Tg-AD mice exhibited the
typical incipient pattern of fibrillar amyloid accumulation, primarily in the
form of small sparse deposits (Figure 1A).
However, no immunoreactivity was observed in any brain region of the newborn
double-transgenic mice between 0-1 month of age (Figure 1B). The main affected areas were completely devoid of Aβ
deposits, and no other related hallmarks were identified in these 2xTg-AD mouse
models.
Aβ plaques in
transgenic models of 4-6 months of age
The incipient Aβ deposits observedbetween 4 and 6 months of age (Figure 1C-D) in the neocortex of
2xTg-AD mice (APP/PS1) presented a simple oligomer structure mainly located at
the inner layers of the cortex and dentate gyrus (Figure 1D). Although these Aβ deposits were sparse and low in
density they already formed a conspicuous hallmark in the 2xTg-AD mouse brain
regions. However, 3x-Tg-AD mice from 4 to 6 months of age exhibited a large
density of Aβ immunoreactive plaques with a dense core (Figure 1C), although with a sparse structure. These deposits were
Type 1-like plaques formed by aggregates of weakly Aβ-immunoreactive material
with a reticular appearance (Figure 1C).
The Aβ deposits in both models were located in the cortex and dentate
gyrus, although in different densities in each model.
Aβ plaques in
transgenic models of 12 months of age
Aβ plaques in triple-transgenic mouse brains were observed in great
density in the neocortical layers and dentate gyrus, showing a more complex
structure than in early stages (Figure
1E). The morphological structure of these Aβ plaques still resembles the
Type-1-like morphological classification that has been described as a mesh of
stained fibrils with a larger area, although they showed a more conspicuous and
enlarged deposition area. In double-transgenic mice, however, the plaques were
detected in similar density in both affected regions (Figure 1F), cortical and hippocampal layers of mouse brain
sections, and their density and dimensions were not comparable to those
observed in triple models.
DISCUSSION
The aim of this study was to describe the comparative development of
the main AD hallmark in a novel triple-transgenic model (APP/BIN1/COPS5) and a
double-transgenic model (APP/PS1).The Aβ peptides are believed to play a
crucial role in AD neuropathology [30,31], mainly in the loss of cognitive
function in AD patients. Consistent with results obtained in previous studies
[32,33], our present results showed a great difference in Aβ production and
deposition in the hippocampus of triple-transgenic mice (APP/BIN1/COPS5), when
compared with double-transgenic mice (APP/PS1) of the same age. Recently, the
3×Tg mouse model for AD, which displays both Aβ and tau hallmark accumulation,
was used to study pathological changes in AD. Though long-term wheel running
was shown to enhance neuroprotection in 3×Tg-AD mice, the traditional markers of
AD neuropathology were not altered [34,35]. However, the rotarod test lasting
for 11 months increased neurogenesis at 20 months of age in 3×Tg-AD mice [35],
while 6 months of rotarod testing reduced oxidative stress and improved
synaptic function in the 7-month-old 3×Tg-AD mice [34]. The mouse strain
differences observed in the present study may play a crucial role in these
divergent results. According to a previous study, Aβ plaques can be detected in
the cortex and hippocampus of double-transgenic mice (APP/PS1) as early as 4-6
months of age, and amyloid plaque burden increases with age [36]. Several lines
of evidence indicate that through the non-amyloidogenic α-secretase pathway,
APP protein is cleaved to produce the sAPPα fragment [37], which is beneficial
for neuronal survival [38,39], whereas through the amyloidogenic α-secretase
pathway, APP protein is cleaved to form neurotoxic Aβ, which is involved in AD
pathogenesis. APP processing can be modulated by different mechanisms,
including but not limited to an altered APP expression, as well as
expression/activity of secretase involved in APP processing. In the current
study, we observed a significant difference in the expression of soluble
oligomers of amyloid β (Aβ) between the double- and triple-transgenic mouse
strains. Accordingly, we propose that the genetic combination of APP, Bin1 and
COPS5 AD-related genes may modulate APP-processing through the changes in
α-secretase and α-secretase activity. Previous genome-wide association studies
have demonstrated that these specific genes have been identified as the most
associated loci for the neurodegenerative process of AD. Therefore, it is known
that BIN1 undergoes complex alternative splicing to generate multiple isoforms
with diverse functions in multiple cellular processes including endocytosis,
membrane remodeling and the potential for a role of BIN1 in the membrane
remodeling that accompanies the process of myelination [40]. Moreover, BIN1
increases cellular BACE1 levels through impaired endosomal trafficking and
reduces BACE1 lysosomal degradation, resulting in increased Aβ production [41].
On the other hand, Wang and colleagues [42] demonstrated previously that COPS5
regulates Aβ generation in neuronal cell lines in a RanBP9-dependent manner,
since by 12 months, COPS5 overexpression in APΔE9 mice (APΔE9/COPS5-Tg)
significantly increased Aβ40-42 levels in the cortex and
hippocampus. They have also proved that COPS5 robustly increased Aβ generation,
followed by increased soluble APP-β (sAPP-β) and decreased soluble-APP-α
(sAPP-α) levels. In particular, they observed that down-regulation of COPS5 by
siRNAs reduced Aβ generation, implying that endogenous COPS5 regulates Aβ
generation. Finally, COPS5 levels were significantly increased in AD brains and
in APΔE9 transgenic mice, and overexpression of COPS5 strongly increased RanBP9
protein levels by increasing its half-life. Taken together, these studies
suggest that COPS5 increases Aβ generation by inducing APP processing and Aβ
generation by stabilizing RanBP9 protein levels [42].
In the present study, we have demonstrated clear differences in the
appearance, structure, density and amount of Aβ deposits between the two
transgenic mouse models evaluated. Numerous lines of transgenic mice are
available for AD research, and many variables, including the number and choice
of transgenes, the promoters used, the background strain and the sex of the
animals, affect the pathology expressed by different mouse lines [43].
Moreover, the structures of Aβ deposits also vary markedly depending on the
genetic factors mentioned above. Tg2576 mice reportedly already exhibit
increased Aβ plaque deposits at 9 months of age [44]. However, in the present
study, sparse fibrillar deposition became visible at 0-1 months of age in
triple-transgenic mice, although their staining intensity was much weaker than
that observed in later developmental stages. Overall, development of Aβ
deposits in triple-transgenic mice was surprisingly early and fast, and
therefore this model appears crucial for amyloid imaging studies. In
double-transgenic mice (APPswe-PS1dE9), incipient Aβ deposition was visible at
4-6 months of age and at 9 months in high immunohistochemical intensity. In
triple-transgenic mice, Aβ deposition was fast during brain development,
although it was more diffuse than fibrillar Aβ. In double-transgenic mice with
mutations in both APP and PS1, the deletion of PS1 exon 9 reportedly results in
PS1 gain of function and the occurrence of large, homogeneous plaques that are
only slightly congophilic stained [45]. Severe Aβ deposition was observed in
the triple transgenic mice of 6 months of age, a finding that does support the
use of this model for brain neuropathological reference region-based analysis.
CONCLUSION
In conclusion, our
present findings demonstrate that the combination of APP, Bin1 and COPS5 genes
plays a crucial role in the onset of neurodegenerative AD hallmarks,
particularly in the early development of Aβ plaques. This study shows that the
insertion of the three AD-related genes involved in the development of Aβ
pathogenesis improves hallmark expression in mice and reduces the time for
their appearance in the affected brain regions of neocortex and hippocampus.
When compared with double-transgenic mice (APP/PS1), this triple-transgenic
model showed an early onset of the Aβ developmental pattern, leading to a more
robust AD animal model. Taken together, our results
indicate that APP, Bin1 and COPS5 may acceleratethe onset of the amyloidogenic
pathway and modulate theprocessing of APP deposition in the mouse brain.
However, additional studies are required to address fully the potential ofthis
new triple-transgenic mouse modelin the preclinical study of AD-like symptoms
and pathology.
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