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Animal Model |
From the Department of Neuropathology and Neuroscience,*
Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo,
Japan; the Alzheimer Disease Research Unit,
Massachusetts General Hospital, Charlestown, Massachusetts; the Nathan
Kline Institute,
New York University,
Orangeburg, New York; the Laboratory for Proteolytic
Neuroscience,§
Brain Science Institute,
RIKEN, Wako, Japan; the Center for Clinical and Molecular
Neurobiology,¶
Departments of Neurology and
Neuroscience, the University of Minnesota, Minneapolis, Minnesota; and
the Department of Pathological Sciences,||
the University
of Manchester, Manchester, United Kingdom
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recently, double-transgenic mice expressing both mutant PS1 and mutant ßAPP were established.23,24 Aß accumulation in brain was accelerated in these mice,23,24 supporting the notion that the primary pathogenic mechanism of mutant PS1 genes is to promote Aß deposition in vivo. It remains unknown if neuronal loss, perhaps clinically the most important lesion in AD brains, occurs in these double-mutant transgenic mice. In this study, we examined brains of PSAPP mice24 expressing both AD-associated mutant PS1 M146L and Swedish-type mutant ßAPP by morphometry, and analyzed the relationship between the age-related deposition of Aß and neuronal loss.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Hemizygous transgenic mice that express K670N/M671L ßAPP (Tg2576:25 APPsw mice) and hemizygous transgenic mice expressing mutant human PS1M146L (mt PS1 mice)3 were crossed, and offspring with four different genotypes, ie, mt PS1/APPsw (PSAPP mice), APPsw mice, mt PS1 mice, and nontransgenic (non-tg) mice, were obtained as previously described.24,26 Non-tg littermates, together with singly transgenic mt PS1 and APPsw offspring, were used as controls for the double-mutant PSAPP mice. A total of 57 (38 at the Tokyo lab and 19 at the Boston lab) mice were examined by quantitative anatomical methods. For the analysis of frontal neocortex (Fc), we used 34 mice in total: four PSAPP and four non-tg mice at ages of 3 and 12 months, two PSAPP and two non-tg mice at 6 months, one PSAPP and two non-tg at 9 months, as well as two mt PS1 and two APPsw mice at ages 3, 6, 9, and 12 months (except three mt PS1 mice at 3 months) were analyzed; in addition, a small number of very old mice (one 19 months PSAPP, two mt PS1 of 19 and 24 months, respectively, and one 24-month non-tg) also were similarly studied. An additional 19 animals were investigated at 12 months of age (five non-tg, four APPsw, six mt PS1, and four PSAPP) for amyloid burden, analysis of CA1 neurons, and synaptophysin immunohistochemistry.
Tissue Preparation
Two parallel studies were carried out in Tokyo (frontal cortex) and in Boston (CA1), using slightly different histological protocols. Because the studies use complementary approaches to test the same hypotheses, we have combined the studies into a single report.
For the analysis of Fc, mice were sacrificed by cervical dislocation, and the brains were removed and fixed by immersion in 70% ethanol/150 mmol/L NaCl for 2 weeks.26 The brains were then cut coronally into five blocks, dehydrated in pure ethanol, and embedded in paraffin, so that coronal sections at the levels of anterior striatum, anterior hippocampus, middle hippocampus, and brainstem appear on one slide. Serial sections were cut at 6-µm thickness.
For the analysis of CA1, mice were anesthetized and brains removed and drop-fixed in 4% paraformaldehyde in phosphate-buffered saline, pH 7.0, for 1 day at 5°C then stored in 10% glycerol in Tris-buffered saline at 5°C before preparing 40-µm coronal microtome sections.
Antibodies, Immunohistochemistry, and Synaptophysin Quantitation
Aß immunostaining was performed using antibody 9204, an affinity-purified rabbit polyclonal antibody raised against amino acid residues 1 to 5 of human Aß specifically reacting with the amino terminus of human Aß starting at L-Asp,26-28 or biotinylated monoclonal anti-Aß 3D6 1:750 (bi-3D6; gift of Elan Pharmaceuticals, South San Francisco, CA).19,29 Sections were immunostained by a standard avidin-biotin complex method using diaminobenzidine as chromogen, and lightly counterstained with hematoxylin.
Synaptophysin immunostaining was performed on the 40-µm floating sections using rabbit anti-synaptophysin 1:120 (DAKO, Carpinteria, CA) and cy3-anti-rabbit IgG 1:200 (Jackson, West Grove, PA). Sections were viewed under a 20x objective on a Nikon TE 400 microscope with a laser confocal scanning system MRC 1024 (Bio-Rad, Wattford, UK). The cy3 signal (excitation wavelength 568 nm, emission wavelength 605 nm) was collected under linear conditions, accumulating six images in the photon counting mode (3% laser, iris 3.0, gain 1500, and black level 0). From each case, fields from the frontal cortex and dentate gyrus were collected from three sections. The images were transferred to NIH Image (National Institutes of Health, Bethesda, MD), where mean pixel intensity was determined for each anatomical region (frontal cortex, and inner, middle, and outer molecular layer of dentate gyrus) and adjusted for background (cy3-anti-rabbit staining alone). Synaptophysin immunoreactivity was assessed in an analysis of variance (ANOVA) by genotype and brain region. The study was powered to have an 80% probability of detecting a 25% difference in pairwise comparisons.
Morphometric Analysis
Frontal cortex neuron counts were performed in four 6-µm cresyl violet-stained sections spaced 42 µm apart within the anterior frontal cortex. Volume density was obtained from an anatomical region of cortex extending laterally 680 µm from the lateral margin of the cingulate. Neuron counts were obtained from 170-µm x 215-µm sampling boxes, carefully ensuring that neurons were not double-counted, throughout this entire anatomical field of superior Fc. Using a 40x objective lens, all neurons with a visible nucleolus were counted. The estimation of total Fc neurons was calculated by multiplying the volume density of the neurons by the volume of the frontal cortex with margins defined as: anterior (anterior extent of corpus callosum); posterior (posterior extent of corpus callosum); medial (medial margin of cingulate cortex); and lateral (dorsal margin of piriform/entorhinal cortex. Fc neuron counts are reported for both hemispheres.
CA1 neuron counts were performed in 40-µm cresyl violet-stained sections spaced 240 µm apart through the entire CA1 region of the hippocampus from one hemisphere using the optical disector technique.30 The entire CA1 was systematically random sampled with approximately 25 optical disectors (25-µm x 25-µm sampling box with extended exclusion lines) under 100x oil objective. CA1 neuron counts are reported for a single hemisphere. The coefficient of error from the counting technique in cortex and CA1 was <0.10,31 suggesting that a minimal amount of variance in the neuronal counts is from the sampling and counting technique. Pilot experiments performed to estimate the total number of neurons in Fc using both the exhaustive sampling technique in the thin sections and the optical disector/systematic random sampling in the thick sections showed that estimates from the two tissue preparations agreed within 20% (Irizarry MC, data not shown).
Power analysis showed that studying four animals of each genotype at each time point would give a statistical power sufficient to have an 80% chance of detecting a 20% loss of neurons. Data on neuron counts of PSAPP and non-tg mice at the ages of 3 months and 12 months were statistically analyzed by StatView-J.4.11 (Abacus Concepts, Berkeley, CA).
Amyloid deposition was evaluated by quantitating the total percentage of cortical surface area covered by Aß immunoreactivity (percent amyloid burden).32 In Fc, four 6-µm sections adjacent to those used for neuron counting were immunostained with antibody 9204, and the amyloid burden was calculated and averaged using the Olympus Image analyzer SP500 (Olympus, Tokyo, Japan).7,8,10 For amyloid burden determination in multiple additional regions (dentate gyrus molecular layer, CA1, entorhinal cortex, cingulate cortex) of the 12-month mice, the total percentage of the regional surface area covered by amyloid deposition over one to three 40-µm sections was determined by bi-3D6 Aß immunostaining using a Bioquant image analysis system (R&M Biometrics, Nashville, TN).19,29 Video images were captured and a threshold optical density was obtained that discriminated staining from background, with manual editing to eliminate artifacts.19,20
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Aß deposits were detected in the cingulate, superior frontal,
and parietal neocortices and occasionally in hippocampus of 3-month-old
PSAPP mice as relatively compact, round plaques of ~20 to 30 µm in
diameter (Figure 1A)
. At 6 months of age,
some compact plaques of ~50 to 70 µm in diameter, which were
occasionally associated with multiple central cores and tiny daughter
deposits, were scattered in the cortex (23.3/mm2)
and small, rather diffuse deposits also were observed (Figure 1B)
. At 9
months (Figure 1C)
and 12 months (Figure 1D)
of age, round, dense
plaques of relatively larger sizes (~100 to 150 µm in diameter) and
increased number (53.3/mm2
at 9 months and
60.0/mm2
at 12 months), and numerous small,
diffuse deposits of irregular shape occupied the neuropil of the
entire neocortex. The density of small deposits was increased at 12
months compared to those at 9 months. Diffuse deposits often contained
neurons within the immunostained areas, although no apparent
cytopathological changes were observed within the somata of these
neurons by conventional histology (cresyl violet or hematoxylin and
eosin; not shown) or immunohistochemistry (eg, 
immunostaining with
antibody AP422 specific for phosphorylated at residue 422 that is
specifically phosphorylated in paired helical
filaments33
), although puctate AP422
immunoreactivity in the margins of cored plaques in the 12-month-old
mice suggests neuritic changes harboring abnormally
phosphorylated (Figure 2)
. In
APPsw mice, very few isolated compact plaques were detected (~1 to 2
in total neocortical areas) at 6 months; some compact plaques as well
as tiny deposits appeared at 9 months of age (Figure 1E)
, and the
number of these plaques increased at 12 months (Figure 1F
;
8.3/mm2), as previously
described.20,25
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. In APPsw mice, average levels of
superior Fc (sFc) amyloid burden were 0.04% at 9 months and 1.4% at
12 months, respectively (Figure 1G)
. No Aß deposits were observed in
mt PS1 mice or non-tg mice of all ages. A detailed analysis of regional
amyloid burden in 40-µm sections from multiple brain areas (molecular
layer of the dentate gyrus, CA1 hippocampal subfield,
cingulate/retrosplenial cortex, and entorhinal cortex) was also
undertaken at 12 months of age (Figure 3)
. Non-tg and mt PS1 transgenic
mice did not contain any amyloid deposits. The APPsw mice had amyloid
burdens ranging from 0.41 to1.68% (Figure 3, B and C)
. PSAPP mice had a 19- to
73-fold increased amyloid deposition compared to the corresponding
regions of the APPsw mice, with amyloid burdens in the range of 18 to
37% (Figure 3, A and C)
.
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Cresyl violet-stained cerebral cortices and CA1 of PSAPP mice,
especially of those in the older ages of 9 to 12 months, showed some
disorganization in the cytoarchitecture of cortical neuronal layers
(Figure 4A)
compared to that of non-tg
mice (Figure 4B)
, which may reflect generalized neuronal loss, focal
loss of neurons within the plaques, or displacement of neurons by
large, dense plaques (Figure 4A
, arrows). To assess for significant
neuronal loss, we performed neuron counts in the frontal cortex and
CA1. No cytopathological changes, eg, nuclear condensation or
neuronophagia, were observed by conventional histological examination
as described above.
|
,
as assessed by two-way ANOVA (transgenic status P =
0.312; age P = 0.228). Of note, 12-month PSAPP mice had
a 2 to 20% reduction in neurons compared to non-tg, PS1, or APPsw
mice. In accord with these results, Fc neuron counts in substantially
older mice (PSAPP 19 months: 5.26 x 106, mt
PS1 19 months: 6.51 x 106; 24 months:
5.85 x 106, non-tg 24 months: 6.34 x
106
for both hemispheres) were comparable to
those in animals of 3 to 12 months.
In the evaluation of neuronal counts in CA1, where the anatomical
boundaries could be clearly defined and there is generally a
homogeneous cell layer, we used a systematic random sampling procedure
through thick sections spanning the entire CA1 region, with an average
coefficient of error for the counting technique of 0.06. There were no
statistically significant differences in CA1 neurons between the four
groups examined at 12 months, although the PSAPP mice had an 8 to 10%
reduction (ANOVA P = 0.44, pairwise P =
0.11 to 0.29) in neurons in CA1 compared to the non-tg, PS1 or APPsw
mice (Figure 5C)
. In the PSAPP mice,
compact amyloid plaques were associated with glial rings and
occasionally disrupted the neuronal lamina (Figure 5A)
relative to
non-tg mice (Figure 5B)
.
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To determine whether the cortical and hippocampal disorganization
produced by amyloid plaques resulted in a net loss of synaptophysin
immunoreactivity, we performed confocal quantitation of synaptophysin
immunohistochemistry in the molecular layer of the dentate gyrus and
the frontal cortex. There were no differences in synaptophysin
immunoreactivity (Figure 6A)
. Cored
amyloid plaques in the PSAPP mice had reduced signal in the core and
were surrounded by enlarged synaptophysin immunoreactive structures
consistent with dystrophic neurites (Figure 6B)
.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-positive
neuritic changes associated with plaques, laminar disorganization,
synaptic disruption, and possible neurotoxicity of fibrillar cored
plaques19,20
) clearly demonstrate the adverse consequences
of Aß deposition in APPsw and PSAPP transgenic mice.
Our data also demonstrate that there is not a dramatic effect on global
synaptophysin immunoreactivity in the APPsw and PSAPP mice. Although
synaptophysin immunoreactivity and synaptic density are consistently
reduced in human AD cortex and hippocampus,34
the effects
on synaptic density by APP transgenes, Aß production, and Aß
deposition have varied in different transgenic mouse lines. Compared to
non-tg mice, increased cortical synaptophysin or cholinergic terminals
have been found in mice expressing human APP under the neuron-specific
enolase promoter,35
in young APP23
mice,36
and in 8-month-old APPsw (Tg2576)
mice;37
reduced synaptophysin or cholinergic terminals
have been identified in mice expressing hAPPV717F under the PDGFß
chain promoter at both young and old ages,38
and in
frontal (but not parietal and entorhinal) cortex of 8-month PSAPP
mice;37
and no change found in synaptophysin
immunoreactivity in 16-month Tg2576 mice compared to non-tg
mice.20
Increased synaptophysin signal from dystrophic
neurites associated with compact plaques may confound reduced
synaptophysin immunoreactivity from synaptic loss (Figure 6B)
.
In vitro experiments using primary cultured neurons have shown that the aggregated, fibrillar form of Aß is neurotoxic under culture conditions.39,40 Accumulating evidence also suggests that increase in the production and deposition of Aß, especially that of the most aggregable Aß42 species caused by mutations in ßAPP or PS genes in early-onset familial AD, is one of the most important pathogenetic factors in AD,2-7 although some nondemented aged individuals harbor abundant cortical Aß deposits without apparent neuronal damage.41,42 Our observation that Aß deposits including Congo Red-positive24 compact plaques in PSAPP mice did not cause a generalized neuronal loss suggests that deposition of Aß alone may not be sufficient to cause further AD changes including neuron loss and neurofibrillary tangle formation.
The pathological mechanisms whereby mutations in PS genes lead to AD may not necessarily be mediated by Aß alone. Other possible mechanisms, including promotion of apoptosis, have been suggested in cells and transgenic mice overexpressing mt PS143,44 or PS2.45,46 It has recently been reported that transgenic mice singly expressing PS1 L286V or H163R under the HeLa PDGFß2 promoter on a FVB/N background develop hippocampal and frontal cortex neuron loss without extracellular Aß deposition at 14 to 17 months of age.22 By contrast, the transgenic line used in our studies, which overexpress PS1 M146L driven by the human PDGFß chain promoter in the C57B6 strain, did not show any neuronal loss or cytological disruption of the cortex, using an exhaustive sampling technique in Fc and a systematic random sampling technique in CA1. This suggests that the PS1 mutant effect on neuronal loss may be modified by specific mutation, promoter, and background strain, and is not a priori generalizable to other systems, including the PS1 M146L line used in this study which nonetheless exhibits a powerful biological effect in accelerating Aß deposition when crossed with APP transgenic mice.
Recently, a number of genetic and acquired risk factors have been
implicated in neuronal death in AD brains. For example, the discovery
of a familial dementing disorder, FTDP-17, linked to mutations in the
gene strongly suggest that dysfunction plays a critical role in
dementing disorders.47,48
Apoptosis49
or
brain injury50
are highlighted as predisposing factors in
AD. Crossing transgenic mice that overexpress other risk genes for AD
with the PSAPP mice, or exposure of PSAPP mice to various acquired risk
factors, are promising strategies to clarify the factors in addition to
Aß necessary for neuronal death in AD.
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Acknowledgements |
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Footnotes |
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Supported by Grants-in-Aid from the Ministry of Health and Welfare, the Ministry of Education, Science, Culture and Sports, and Core Research for Evolutional Science and Technology (CREST) of Japan Science and Technology Corporation, Japan, and a grant from the National Institutes of Health (AG00793).
A. T. and M. C. I. contributed equally to this study.
Accepted for publication April 3, 2000.
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