(American Journal of Pathology. 2001;158:173-177.)
© 2001 American Society for Investigative Pathology
ß-Site APP Cleaving Enzyme mRNA Expression in APP Transgenic Mice
Anatomical Overlap with Transgene Expression and Static Levels with Aging
Michael C. Irizarry*,
Joseph J. Locascio
and
Bradley T. Hyman*
From the Alzheimer Disease Research Unit,*
Massachusetts General Hospital, Charlestown; and the Department of
Brain and Cognitive Sciences,
Massachusetts
Institute of Technology, Cambridge, Massachusetts
 |
Abstract
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The principal enzyme responsible for the ß-site cleavage of
amyloid precursor protein (APP) in the brain is a membrane-bound
aspartyl protease ß-site APP cleaving enzyme (BACE). We examined
human APP (hAPP) and BACE mRNA expression by in situ
hybridization in young and old hAPP transgenic mice from two lines:
Tg2576, hAPP KM670–671NL (hAPPSw) at 4 and 15
months; and PDAPP, hAPP V717F, at 4 and 11 months. In
transgene-positive mice from both lines, hAPP expression was
most prominent in cortical, cerebellar, and hippocampal
neuronal populations. Cingulate, entorhinal, and
hippocampal amyloid burden in transgene-positive 16-month Tg2576 mice
was 4 to 8%, and in 12-month PDAPP mice, 2 to 4%;
there was no cerebellar amyloid deposition. BACE expression in
transgenic and nontransgenic mice was highest in the cerebellar granule
cell layer and hippocampal neuronal layers, intermediate in
cortex, lower in subcortical regions, and minimal or
absent in white matter of the cerebellum. Emulsion-dipped sections
confirmed a predominantly neuronal pattern of expression. The amount of
hybridization signal did not differ between transgenic and
nontransgenic mice, or young and old mice, within each
line. Thus, hAPP and endogenous BACE expression in similar
anatomical localizations allow for processing of hAPP and Aß
formation in hAPP transgenic mice, but these are modified by
additional age-related and anatomical factors.
|
Introduction
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Alzheimer’s disease is characterized pathologically by amyloid
ß protein (Aß) deposition, neurofibrillary tangle formation, and
neuronal loss in specific neuroanatomical regions. Transgenic mice
expressing mutant human amyloid precursor protein (hAPP) have been
developed as animal models of Alzheimer’s disease.1
Several lines of hAPP transgenic mice develop cerebral amyloid deposits
with aging,2-7
including the PDAPP mouse expressing an
hAPPV717F minigene under the human
platelet-derived growth factor b-chain (PDGFb) promoter,2
and the Tg2576 mouse expressing the 695-amino acid isoform of hAPP with
the KM670–671NL Swedish double mutation (hAPPSw)
under the hamster prion protein (PrP) promoter.3
Two
remarkable features of both of these hAPP transgenic mice are (i) that
Aß deposits occur only in aged animals, and (ii) that the Aß
deposits occur in a restricted set of characteristic locations in the
cortex and hippocampus. The sites of amyloid deposition
do not reflect the regional expression of either the
hAPPSw or hAPPV717F
transgenes, which are widely expressed in neurons throughout the
brain.8,9
Of interest, however, is that the anatomical
pattern parallels the pattern seen in human Alzheimer’s disease, where
amyloid plaques occur in a stereotyped distribution in the neocortex
and hippocampus, including the outer molecular layer of the dentate
gyrus. These results imply that other factors, in addition to hAPP
expression, impact the location and age dependency of Aß generation
and deposition in hAPP transgenic mice.
Aß is produced from proteolytic processing of APP by the action of
- and ß-secretases. Presenilin-1 is essential for the
-secretase cleavage of APP.10
Presenilin-1 is widely
expressed in the human and mouse brain, overlapping with APP, but with
highest expression in areas that do not develop Aß deposits, such as
the cerebellum.11
Moreover, presenilin-1 mRNA levels are
highest in the embryo, then decline markedly to remain stable with
increasing age.12,13
Thus, presenilin-1 expression
patterns do not correlate well with the anatomical pattern or age
relationship of Aß deposition.
Recently, the enzyme responsible for the ß-site cleavage of APP in
brain has been identified as BACE. BACE is a 501-amino acid
membrane-bound aspartyl protease with an acidic pH optimum, widely
expressed in the brain, pancreas, and other tissues,14-17
localized in neuronal cell bodies and proximal
dendrites,17
and colocalizing with Golgi and endosomal
markers.14,15
A homologous protein, BACE2,18
may also cleave APP,19
but is expressed in very low levels
in the adult human and rat brain.19,20
Because BACE is the
principal ß-secretase in neural tissues, we assessed BACE mRNA
expression by in situ hybridization in the hAPP transgenic
mouse models described above. We asked if the age and region dependence
of Aß deposition could be explained by patterns of BACE expression
with age, or in brain regions susceptible to amyloid deposition; we
also examined whether BACE expression was altered by overexpression of
its substrate, hAPP, in transgenic mice.
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Procedure
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Transgenic Mice and Tissue Preparation
Tg2576 mice were bred from lines described
previously.3,9
The transgene is expressed in C57B6/SJL F1
mice backcrossed to C57B6/SJL breeders. Age-matched nontransgenic
littermates served as controls. Three to six heterozygote transgenic
and six nontransgenic mice were studied at ages of 4 and 15 months for
in situ hybridization (total of 3 male and 6 female
transgenic and 8 male and 4 female nontransgenic). Four from each group
were studied at 16 months for amyloid burden, as published
previously.9
Heterozygous PDAPP transgenic mice were bred from the previously
established line PDAPP-109 over several generations on hybrid
backgrounds representing combinations of C57BL/6, DBA, and
Swiss-Webster strains.2,21,22
Four heterozygous
transgenic and four nontransgenic littermates were studied at 4 months
and 11 months of age (total of 4 male and 4 female transgenic mice, 4
male and 4 female nontransgenic mice). Four from each group were
studied at 12 months for amyloid burden, as published
previously.8
Mice were sacrificed under CO2 and brains were
removed and snap-frozen in isopentane chilled with dry ice.
Twelve-micron sagittal (for Tg2576 mice) or 14-µm coronal (for PDAPP
mice) cryostat sections from one hemisphere were thaw-mounted onto
polylysine-coated glass slides and stored at -70°C.
In Situ Hybridization
In situ hybridization was performed according to
previously published protocols.8,9,23
Sections were fixed
for 5 minutes in ice-cold 4% paraformaldehyde and stored in 95%
ethanol at 4°C. Sections were hybridized overnight with
[35S]adenosine (DuPont/NEN, Boston, MA)
end-labeled 45-mer oligonucleotide sense and antisense probes (10,000
cpm/µl) for BACE (GenBank AF190726, nucleotides 881 to 925) and
hAPP69524
at 42°C in sealed chambers humidified with
50% formamide/4x standard sodium citrate (SSC) water, then washed in
1x SSC at 55°C. Slides were exposed to Amersham ß-max
autoradiography film (Amersham Pharmacia Biotech, Piscataway, NJ) for 1
to 7 days, then Amersham Hypermax ß emulsion for 3 to 6 weeks, and
counterstained with thioflavin-S (thio-s) and thionin.
Autoradiographic images of coronal sections were captured using a
Bio-Rad (Hercules, CA) GS-700 Imaging Densitometer under maximal
resolution (1200 dpi, pixel depth 12) for relative optical density
measurement using Molecular Analyst software (Bio-Rad). Mean relative
optical density in measurement frames traced over the brain region of
interest was corrected for background. Hybridization with sense probes
yielded no detectable signal.
Statistical Assessment
We used a mixed between (genotype and age)- and within (brain
region)-subject analysis of variance to analyze mRNA signal (mean
relative optical density) in Tg2576 and PDAPP mice (using the SAS GLM
procedure).25
Data were pooled for male and female
animals. In the case of sagittal sections from the Tg2576 mice, brain
regions were dentate gyrus, CA1, CA3, frontal cortex, posterior cortex,
striatum, thalamus, cerebellar granule layer, and cerebellar molecular
layer. In the coronal sections from the PDAPP mice, they were dentate
gyrus, CA1, CA3, entorhinal cortex, cingulate, and thalamus. Degrees of
freedom were adjusted26
to correct for violation of
analysis of variance assumptions of independent errors.
|
Results
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Expression of hAPP mRNA in Tg2576 and PDAPP Mice
Human APP expression in Tg2576 mice and PDAPP mice was prominent
in neurons, with strongest signal in cortical, cerebellar, and
hippocampal neuronal populations (Figure 1, A and B)
. Cortical transgene
expression in the PDAPP mouse was most prominent in cingulate,
retrosplenial, neocortical, and superficial piriform/entorhinal
regions, with less signal in deep piriform/entorhinal cortex. No signal
was detected in nontransgenic mice. Emulsion-dipped sections
demonstrated neuronal expression of the transgene.8,9
This
is consistent with the neuron-specific promoters for these mouse lines.
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Figure 1. hAPP695 mRNA expression (A and
B) and Aß immunoreactivity
(C and
D) in Tg2576
(A and
C) and PDAPP
(B and
D) transgenic mice. In
situ hybridization in sagittal Tg2576 mouse sections
(A) and
coronal PDAPP mouse sections
(B)
demonstrate a neuronal pattern of transgene expression, especially in
cortical and hippocampal neuron layers. Bi-3D6 Aß immunoreactivity in
16-month Tg2576
(C) and
12-month PDAPP
(D) mice
demonstrate cortical
(ctx) and hippocampal
Aß deposits, especially in dentate gyrus
(dg) and CA1. Scale bars,
2 mm (A and
B) and 500 µm
(C and
D).
|
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Aß Deposition in Tg2576 and PDAPP Mice
Amyloid deposition in heterozygous 16-month Tg2576 mice showed a
characteristic anatomical pattern (Figure 1, C and D)
. Amyloid
burden (the percentage of surface area of an anatomical region covered
by Aß immunoreactivity) using the antibody bi-3D6 was 4% to 8% in
cingulate cortex, entorhinal cortex, and hippocampus, and absent in
thalamus, basal ganglia, and cerebellum. There were no amyloid deposits
in 4-month Tg2576 mice.9
Amyloid deposition in 12-month PDAPP mice showed essentially the same
pattern. Amyloid burden was 2% to 4% in cingulate and entorhinal
cortex and hippocampus. There were no amyloid deposits in thalamus,
basal ganglia, and cerebellum. Four-month mice did not have any amyloid
deposits.8
Expression of BACE mRNA in Tg2576 and PDAPP Mice
In transgenic and nontransgenic mice, the pattern of BACE
expression was highest in the cerebellar granule cell layer and
hippocampal neuronal layers (dentate gyrus granule cells, CA1 and CA3
pyramidal cell layer), with intermediate expression in the cortex,
lower levels in the subcortical regions, and lowest in the white matter
of the cerebellar molecular layer (Figures 2–4)
.
The intensity of BACE signal corresponded to neuronal density, with the
highest signals in the highly packed pyramidal and granule cell layers
of hippocampus and cerebellum. Emulsion-dipped sections confirmed the
neuronal expression of BACE, with absent or minimal glial expression
(Figure 3)
. Cored plaques labeled by thio-S in the Tg2576 mice and
PDAPP mice also bound the BACE mRNA probe. However, most of these
plaques were not associated with any thionin-labeled cellular
structures, apart from nearby neurons, suggesting nonspecific binding
of the mRNA probe to compact plaques, although we cannot exclude
specific binding to neuronal BACE mRNA trapped in
plaques.27
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Figure 2. BACE mRNA expression in young and old Tg2576 and PDAPP transgenic and
nontransgenic mice demonstrates cortical, subcortical, and hippocampal
BACE expression. Cored plaques also bind the probe
(Scale bars, 2 mm).
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Figure 3. Emulsion-dipped BACE in situ hybridization with thionin
counterstain demonstrates neuronal expression of BACE mRNA in 15-month
transgenic Tg2576 mouse cortex
(A) and
11-month transgenic PDAPP mouse CA3
(B). Scale
bar, 10 µm.
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Figure 4. Quantitation of regional BACE mRNA expression
(film relative optical density (ROD) above
background ± SEM) by in
situ hybridization in Tg2576
(A) and PDAPP
(B) mice.
n = 3 to 6 in each group, as shown in legend. dg,
dentate gyrus; fr ctx, frontal cortex; post ctx, posterior occipital
cortex; str, striatum; thal, thalamus; cb grn, cerebellar granule cell
layer; cb mol, cerebellar molecular layer; cing, cingulate cortex.
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We compared the BACE pattern of expression to that seen for the hAPP
transgene, to test the hypothesis that endogenous BACE acts on hAPP to
generate Aß. hAPP695 mRNA is more robustly expressed. The regional
distribution of hAPP matches closely that of BACE, suggesting that hAPP
and BACE are expressed in overlapping brain regions. Comparing this
pattern of overlap to the pattern of Aß deposition, however, suggests
that although coexpression of hAPP and BACE is necessary, it is not
sufficient for Aß deposits. Coexpression of hAPP and BACE mRNA in
hippocampus and cortex is associated with amyloid deposition in these
regions, but prominent coexpression in the cerebellar granule cell
layer does not result in cerebellar amyloid plaques.
The transgenic Tg2576 mice do not develop amyloid deposits until 9 to
11 months of age; the PDAPP mice do not develop them until 6 to 9
months of age. To determine whether alterations in BACE expression with
hAPP expression or aging could contribute to the development of amyloid
deposition in these mice, we compared BACE mRNA levels in transgenic
and nontransgenic mice before amyloid deposition (4-month Tg2576 and
PDAPP) and after amyloid deposition (15-month Tg2576 and 11-month
PDAPP) (Figure 4)
. In the case of analysis of variance for the Tg2576
mice as well as that for the PDAPP mice, the only significant effect
found was a main effect for brain region (P <
0.0001), reflecting expected differences in BACE mRNA levels among
regions. No significant genotype or age effects, or interactions
involving them, were found. Thus, BACE hybridization signal did
not differ between transgenic mice and nontransgenic mice, or with
aging, and overexpression of hAPP did not alter BACE expression.
|
Discussion
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The pattern of BACE expression closely matches the regional
expression of the hAPP transgenes, demonstrating that both the hAPP and
endogenous BACE are expressed in overlapping brain regions, and that
the hAPP may therefore be susceptible to processing by endogenous BACE.
Although BACE and hAPP expression are high in cortical and limbic areas
that develop Aß deposition, high expression is also seen in the
cerebellum, which does not develop significant amyloid deposition,
indicating that other regionally specific factors are necessary. We
tested the hypothesis that the age and anatomical specificity of Aß
deposition in hAPP transgenic mice is related to overlap of hAPP and
its processing enzymes. Our data show that this is not necessarily the
case. The coexpression of APP and BACE supports a role for BACE in Aß
generation; however, it cannot account for the anatomical specificity
and age dependence of Aß deposition. Although it is difficult to
extrapolate from mRNA levels to protein levels and enzyme functional
activity, these results support previous studies looking at the
ß-cleaved metabolite of APP (APP-ß) produced by BACE, which does
not vary with age in the hippocampus, cortex, and cerebellum of
transgenic PDAPP mice.22
The BACE homologue, BACE2, may
process APP, but it is only present in low levels in brain, and is
responsible for a small proportion of ß-secretase activity by cell
culture relative to BACE.18
Thus, hAPP and endogenous BACE
expression in similar anatomical localizations allow for processing of
APP and Aß formation in these hAPP transgenic mice, but the amount,
form, and location of Aß deposition are modified by age and
anatomical factors, as well as additional proteins such as presenilin
and apolipoprotein E.28-31
|
Acknowledgements
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We thank Karen K. Hsiao-Ashe, M.D., Ph.D. (University of
Minnesota) for kindly providing Tg2576 breeders, and Dora Games,
Ph.D., and Dale Schenk, Ph.D. (Elan Pharmaceuticals) for generously
providing PDAPP brain tissue.
|
Footnotes
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Address reprint requests to Dr. Bradley T. Hyman, Alzheimer Disease Research Unit, Massachusetts General Hospital, East, 149 13th Street, Charlestown, MA 02129. E-mail: b_hyman{at}helix.mgh.harvard.edu
Supported by National Institutes of Health grants AG00793 and AG05134 (to Massachusetts Alzheimer Disease Research Center).
Accepted for publication September 14, 2000.
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T. D. Stein and J. A. Johnson
Lack of Neurodegeneration in Transgenic Mice Overexpressing Mutant Amyloid Precursor Protein Is Associated with Increased Levels of Transthyretin and the Activation of Cell Survival Pathways
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H. Fukumoto, B. S. Cheung, B. T. Hyman, and M. C. Irizarry
{beta}-Secretase Protein and Activity Are Increased in the Neocortex in Alzheimer Disease
Arch Neurol,
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J.-T. Gau, M. L. Steinhilb, T.-C. Kao, C. J. D'Amato, J. R. Gaut, K. A. Frey, and R. S. Turner
Stable {beta}-Secretase Activity and Presynaptic Cholinergic Markers During Progressive Central Nervous System Amyloidogenesis in Tg2576 Mice
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Abstract
Introduction
