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Volume 17, Number 18,
Issue of September 15, 1997
pp. 7053-7059
Copyright ©1997 Society for Neuroscience
A Deposition Is Associated with Neuropil Changes, but not with
Overt Neuronal Loss in the Human Amyloid Precursor Protein V717F
(PDAPP) Transgenic Mouse
Michael C. Irizarry1,
Ferdie Soriano2,
Megan McNamara1,
Keith J. Page1,
Dale Schenk2,
Dora Games2, and
Bradley T. Hyman1
1 Department of Neurology, Massachusetts General
Hospital, Boston, Massachusetts, 02114 and 2 Athena
Neurosciences, South San Francisco, California 94080
 ABSTRACT
- INTRODUCTION
- MATERIALS AND METHODS
- RESULTS
- DISCUSSION
- FOOTNOTES
- REFERENCES
ABSTRACT 
The PDAPP transgenic mouse overexpresses human amyloid precursor
protein V717F (PDAPP minigene) and develops age-related cerebral amyloid- protein (A) deposits similar to senile plaques in
Alzheimer's disease. We find age-related cortical and limbic A
deposition that begins at 8 months and progresses to cover 20-50% of
the neuropil in cingulate cortex, entorhinal cortex, and hippocampus of
18-month-old heterozygotic animals. The regional patterns of transgene
expression and amyloid deposition suggest that A deposits occur at
the terminals of overexpressing neurons. Amyloid deposition is
associated with dystrophic neurites and extensive gliosis. However,
stereological analysis shows that there is no overt neuronal loss in
entorhinal cortex, CA1 hippocampal subfield, or cingulate cortex
through 18 months of age. In addition, there is no apparent loss of
mRNA encoding neuronal synaptic, cytoskeletal, or metabolic proteins.
Thus, widespread A deposition in 18-month-old heterozygotic mice
produces neuritic alterations and gliosis without widespread neuronal
death.
Key words:
transgenic mice;
Alzheimer's disease;
hippocampus;
amyloid;
amyloid precursor protein;
cingulate cortex;
entorhinal
cortex;
neuritic dystrophy;
synaptophysin;
microtubule associated
protein-2;
cytochrome oxidase;
glial fibrillary acidic protein
INTRODUCTION
Alzheimer's disease (AD) is
characterized neuropathologically by amyloid plaques, neurofibrillary
tangles, and marked neuronal loss. Amyloid plaques are composed of an
internal fragment of amyloid precursor protein (APP), the 4 kDa
amyloid- protein (A) (Selkoe, 1994 ). Although APP mutations cause
AD (Goate et al., 1991; Mullan et al., 1992), and A is neurotoxic
in vitro (Koh et al., 1990; Mattson et al., 1992; Pike et
al., 1993; Cotman et al., 1994; Cotman and Su, 1996; Yankner and
Lorenzo, 1996), it is uncertain whether A deposition is directly
linked to neurofibrillary tangle formation or neuronal loss in AD
(Gomez-Isla et al., 1997). Recently, animal models of cerebral A
deposition have been developed using transgenic technology (Games et
al., 1995; Higgins et al., 1995; Hsiao et al., 1996). The unique
resource of such transgenic animal models allows us to address several
questions regarding the pathophysiological role of cerebral A
deposition. What underlies the regional anatomic specificity of amyloid
deposition? Does A deposition result in disruption of the neuropil?
Is A neurotoxic in vivo?
The PDAPP transgenic mice (Games et al., 1995) were generated using the
platelet-derived growth factor B promoter driving a human APP (hAPP)
minigene (PDAPP) encoding the V717F familial AD mutation and containing
modified intronic sequences allowing for alternative splicing
(Rockenstein et al., 1995). These mice express the hAPP transgene at
levels fourfold to sixfold higher than endogenous mouse APP
(Rockenstein et al., 1995). Age-related amyloid deposition occurs in a
consistent regional distribution beginning at 6-9 months and
increasing with age (Johnson-Wood et al., 1997), with associated glial
and neuronal morphological alterations (Masliah et al., 1996).
In this report, we examine the relationship between transgene
expression, A deposition, neuronal loss, and mRNA expression in 4- to 18-month-old heterozygotic PDAPP mice. In particular, we test the
hypothesis that neuronal death and dysfunctional mRNA synthesis occur
with aging as a consequence of hAPP V717F overproduction and A
deposition, using techniques of immunohistochemistry, stereology, and
in situ hybridization. In AD brain, these techniques
demonstrate neuritic changes within plaques (Masliah et al., 1993),
neuronal loss in the hippocampal CA1 subfield, entorhinal cortex, and
cingulate cortex (Vogt et al., 1992; West, 1994; Gomez-Isla et al.,
1996a), and loss of neuronal synaptic, cytoskeletal, and metabolic
protein mRNA with upregulation of glial fibrillary acidic protein
(GFAP) mRNA associated with astrogliosis (Clark and Parhad, 1989;
Simonian and Hyman, 1994; Callahan and Coleman, 1995; de la Monte et
al., 1995; Hatanpaa et al., 1996). We find that the same techniques are
easily adapted to the analysis of the PDAPP transgenic mice.
MATERIALS AND METHODS
Transgenic mice. The heterozygote 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 (Games et al., 1995; Masliah et
al., 1996; Johnson-Wood et al., 1997). Age-matched nontransgenic littermates derived from the PDAPP lines were used as controls. For
amyloid burden studies and neuron counts, six transgenic and six
nontransgenic mice at ages of 8, 12, and 18 months were analyzed. For
in situ hybridization studies, four transgenic and four
nontransgenic mice at ages of 4, 11, and 18 months were studied.
Tissue preparation. Mice were anesthetized, and the brains
were removed and snap frozen in isopentane chilled with dry ice. For
in situ hybridization, 14 µm coronal cryostat sections
were thaw-mounted onto sterile Probe-On (Fisher Scientific, Houston, TX) slides coated with a sterile solution of 0.01%
poly-L-lysine and fixed in ice-cold 4% paraformaldehyde in
PBS for 5 min (Sirinathsinghji and Dunnett, 1993). For
immunohistochemistry and stereology, brains were drop-fixed in 4%
paraformaldehyde and post-fixed for 3 d before preparing 40 µm
coronal vibrotome sections.
In situ hybridization. The in situ procedure has
been described in detail (Sirinathsinghji and Dunnett, 1993; Page et
al., 1996). Oligonucleotide probes (45 mer) were synthesized on an Applied Biosystems (Foster City, CA) DNA synthesizer (Page et al.,
1996) or purchased commercially (Life Technologies, Gaithersburg, MD).
The probes used were (mRNA, GenBank accession number, bases): rat
synaptophysin, X06177, 1143-1187; mouse microtubule-associated protein-2 (MAP-2), M21041, 5131-5175; mouse cytochrome oxidase subunit-2 (COX-2), V00711, 7015-7059; mouse cytochrome oxidase subunit-4 (COX-4), S57870, 538-582; and mouse GFAP, K01347, 1784-1828. The probes used for hAPP isoforms are detailed by Sola et
al. (1993).
Fourteen-micrometer coronal fixed cryostat sections were hybridized
overnight with 35S-adenosine (DuPont NEN, Boston, MA)
end-labeled 45 mer oligonucleotide probes (10,000 cpm/µl) at 42°C
in sealed chambers humidified with 50% formamide/0.1%
diethylpyrocarbonate water, and then washed in 1× SSC at 55°C.
Slides were exposed to Amersham (Arlington Heights, IL) -max
autoradiography film for 1-18 d. Hybridization of sections with sense
probes yielded no detectable signal.
Autoradiographic images of coronal sections were captured using a
Bio-Rad (Hercules, CA) GS-700 imaging densitometer under maximum
resolution (1200 dots per inch; pixel depth, 12) for relative optical
density (ROD) measurements using Molecular Analyst software (Bio-Rad).
RODs were measured directly within superimposed measurement frames
across specific CNS loci. The ROD measurements were corrected for
background and averaged for each region over three sections. Data were
analyzed by ANOVA for genotype and region with Fisher's exact
post hoc analysis. The power of our study was sufficient to
have an 80% chance of detecting a 20% loss of neurons or mRNA signal
at a confidence level of 0.05.
Immunostaining. Fixed 14 µm coronal cryostat or 40 µm
vibrotome sections were treated with 0.5% Triton X-100 in
Tris-buffered saline (TBS) for 20 min, blocked with 3% milk in TBS,
and sequentially incubated in primary antibody [rabbit anti-GFAP
(1:500), Sigma, St. Louis, MO; monoclonal anti-hAPP 8E5 (1:100), Athena
Neurosciences, South San Francisco, CA; and biotinylated monoclonal
anti-A 3D6 (1:750), Athena Neurosciences], and secondary antibody
[cy3-anti-rabbit (1:200), Jackson Immunochemicals, West Grove, PA;
BODIPY-fluorescein anti-mouse (1:200), Molecular Probes, Eugene, OR;
and Cy5- or horseradish peroxidase-conjugated streptavidin (1:750),
Jackson, Vector Laboratories, Burlingame, CA]. 3-3 -Diaminobenzidine
was the chromagen for horseradish peroxidase. Confocal images were obtained on the Bio-Rad laser confocal imaging system at an excitation wavelength of 586 nm and an emission wavelength of 605 nm for Cy3, 647 and 680 nm for Cy5, and 488 and 522 nm for BODIPY-fluorescein.
Amyloid burden quantitation. Amyloid deposition was
quantified using A immunostaining [monoclonal 3D6 (Johnson-Wood et
al., 1997), diaminobenzidine reporter] and a Bioquant (Nashville, TN) image analysis system (Gomez-Isla et al., 1996b). Video images of each
anatomic region of interest on 40 µm sections were captured, and a
threshold optical density was obtained, which discriminated staining
from background. Manual editing of each field eliminated artifacts. The
"amyloid burden" defined as the total percentage of cortical
surface area covered by amyloid deposition over three sections was
calculated for CA1, cingulate, dentate gyrus molecular layer, and
entorhinal cortex in each mouse.
Stereology. Neuron counts were performed using the optical
disector technique (West and Gundersen, 1990) in 40 µM
cresyl violet-stained coronal sections spaced 240 µM
apart. The margins of the entorhinal cortex (EC) were defined in a
caudal-to-rostral orientation: caudal, most caudal section containing
white matter; rostral, 1 mm rostrally at the level of caudal extent of
the pyriform cortex; lateral, rhinal fissure; and medial, parasubiculum
(Lorente de No, 1933; Sidman et al., 1971). The entorhinal cortex was
divided into layers I, II, III, and IV-VI (Lorente de No, 1933). The
entire volume of the each EC layer was estimated according to the
principle of Cavalieri (1966), using the Bioquant image analysis
system. Neuronal counts were obtained from a systematically
random-sampling scheme on sections spanning the entire EC. The number
of neurons in the entire EC and each of its lamina was estimated using
~100 optical disectors in each case. Each optical disector was a
25 × 50 µm sampling box with extended exclusion lines. Using a
100× oil immersion lens, neurons with a visible nucleolus were counted if they were not present in the initial plane of focus but came into
focus as the optical plane moved through the tissue. The estimation of
total neurons was calculated by multiplying the volume density of the
neurons in the layers by the volume of the layers. All the counts were
performed by a single examiner (M.C.I.) blinded to transgenic
status.
The caudal retrosplenial/cingulate cortex was sampled in a
caudal-to-rostral orientation: caudal, section containing the most caudal extent of the dentate gyrus; rostral, extending anteriorly 1.2 mm; medially, the subiculum; and laterally, the occipital cortex. This
entire region was sampled in five 40-µm-thick sections taken at
equally spaced intervals (240 µm), using ~25 optical disectors in
each case.
Caudal CA1 was sampled from its caudal extent anteriorly in seven 40 µm sections taken at equally spaced intervals (240 µm), using ~25
optical disectors in each case.
The appropriateness of the sampling schemes chosen was evaluated by
calculating the precision of the estimates made in each mouse,
expressed as the coefficient of error (CE) (West, 1993). The CE of all
cases was <0.10, suggesting that a minimal amount of variance in the
counts is from the technique.
RESULTS
Regional expression of the PDAPP transgene
The PDAPP transgenic mouse expresses the three major hAPP isoforms
containing 695, 751, and 770 amino acids. The isoforms containing the
Kunitz protease inhibitor domains, hAPP751 and hAPP770, respectively,
constitute 46.7 and 45.8% of the total hAPP mRNA (Rockenstein et al.,
1995). The regional expression of the transgene was characterized by
in situ hybridization with 35S-labeled
oligonucleotide probes specific for each isoform in four heterozygote
mice at each age of 4, 11, and 18 months. The expression pattern of
each isoform was similar, with the highest expression in the
hippocampus, followed by the cortex and superficial entorhinal region,
then subcortical regions. White matter, amygdala, and the deep layers
of the entorhinal cortex had little or no transgene expression (Fig.
1). There was no change in the pattern or
levels of expression with age from 4 to 18 months. Emulsion-dipped in situ sections confirmed an exclusively neuronal
expression of the transgene.
Fig. 1.
Expression of hAPP isoforms in PDAPP mice.
In situ hybridization showing similar hAPP695, 751, and
770 mRNA regional distribution in anterior and posterior coronal
sections at 4, 11, and 18 months of age in heterozygote transgenic
mice. Anterior sections demonstrate strongest message in the
hippocampus, followed by the cingulate and cortical regions, and
minimal signal in hippocampal white matter and amygdala; posterior
sections demonstrate in addition strong message in the superficial, but
not deep, layers of the entorhinal cortex. Scale bar, 1 mm.
[View Larger Version of this Image (69K GIF file)]
Regional pattern of amyloid deposition
To assess the regional pattern of amyloid deposition resulting
from transgene expression, we quantitated the amount of A immunoreactivity in the neuropil of selected brain regions of six
heterozygote mice at ages 8, 12, and 18 months (Fig.
2). We focused on the hippocampus,
entorhinal cortex, and cingulate cortex because these are areas of
prominent amyloid deposition both in this transgenic animal and in
human AD (Arnold et al., 1991). Amyloid deposition begins in the
cingulate cortex of PDAPP transgenic mice by 8 months of age (amyloid
burden, 0.4%). At 12 months of age, the amyloid burden of the dentate
gyrus molecular layer, CA1, and cingulate and entorhinal cortex is
2-4%. Between 12 and 18 months of age, there is a profound increase
in amyloid deposition in these regions, with amyloid burden on the
order of 20-50%. By comparison, amyloid burden in the human neocortex
in AD is generally 6-12% (Hyman et al., 1993).
Fig. 2.
Amyloid burden in PDAPP mice. Immunostaining for
A demonstrates age-dependent accumulation of amyloid beginning in
the cingulate cortex (cing) at 8 months
(A), prominent in dentate gyrus
(dg), CA1, and entorhinal cortex (erc) by
12 months (B), and profound deposition in these
regions by 18 months (C), quantitated by percent amyloid burden (±SD) measurements in these regions
(D). Scale bar, 1 mm.
[View Larger Version of this Image (65K GIF file)]
Neuron counts in CA1, cingulate, and entorhinal cortex
We next examined whether there was neuronal loss in these animals.
Using unbiased stereological counting techniques, we assessed laminar
neuronal counts in layers II, III, and IV-VI of the entorhinal cortex.
Six transgenic and six nontransgenic mice at ages of 8, 12, and 18 months, masked for transgenic status, were examined. These ages
correspond to absent, moderate, and severe cerebral A deposition,
respectively. The entorhinal cortex was chosen for analysis because:
(1) the entorhinal cortex undergoes substantial age-related amyloid
deposition in the PDAPP mouse beginning at 10-12 months of age; (2)
amyloid deposits are prominent in the terminal field of its major
efferent projection (the outer molecular layer of the dentate gyrus) by
12 months; and (3) the entorhinal cortex has marked neuronal
depopulation early in AD (Gomez-Isla et al., 1996a). There was no
difference in neuronal counts between the heterozygote transgenic mice
and nontransgenic littermates at any age, whether analyzed layer by
layer or as a whole (Fig. 3). Thus, there
was no detectable neuronal loss in the entorhinal cortex even by 18 months of age, after 6-8 months of exposure to A deposits, when
amyloid burden in the entorhinal cortex is 30%, and that of the
dentate gyrus molecular layer is 50%.
Fig. 3.
Neuron counts in PDAPP mice (±SD). No difference
is noted in layer-by-layer neuronal counts in the entorhinal cortex of
8 (A), 12 (B), and 18 (C) month heterozygote transgenic mice compared with nontransgenic littermates. At 18 months, no significant difference is noted in the caudal CA1 or the caudal retrosplenial/cingulate region
(D). Neuronal architecture is grossly preserved
in wild-type mice (E) compared with nontransgenic
animals (F) despite tremendous amyloid burden
(G; A immunostaining of section immediately adjacent to F). Counts reflect neurons in one hemisphere.
cing, Cingulate cortex; erc, entorhinal
cortex. Scale bar, 175 µm.
[View Larger Version of this Image (65K GIF file)]
Because the majority of A deposits in entorhinal cortex were
morphologically "diffuse," we considered the possibility that neuronal loss would correspond to a more "compact" morphology of
amyloid deposits. We therefore examined two other areas that developed
A deposits with a compact morphology and that are known to have
substantial neuronal loss in AD brains: caudal CA1 hippocampal subfield
(West, 1994) and caudal retrosplenial/cingulate cortex (Vogt et al.,
1992). Neither of these regions in the 18-month-old heterozygote
transgenic animals had detectable neuronal loss (Fig. 3).
Neuronal mRNA synthesis
We also tested the hypothesis that neuronal mRNA synthesis was
altered with amyloid deposition, even if the total neuronal number was
unaffected. Thus, as surrogate measures of neuronal integrity, we
assessed mRNA expression of neuronal synaptic and cytoskeletal
proteins, synaptophysin and MAP-2, and mRNA expression of COX-2 and
COX-4. These were chosen because there is a marked loss of synaptic and
cytoskeletal protein mRNA and COX-2 but not COX-4 mRNA in AD brains,
even in intact neurons (Clark and Parhad, 1989; Simonian and Hyman,
1994; Callahan and Coleman, 1995; de la Monte et al., 1995; Hatanpaa et
al., 1996). There was no loss of regional expression of any of these
mRNA's in four transgenic and four nontransgenic mice at 4, 11, or 18 months of age (Fig. 4). This result
contrasts with immunohistochemical data revealing a regional loss of
both synaptophysin and MAP-2 immunoreactivity (Games et al., 1995),
suggesting that neurons of origin with intact soma may have compromised
axonal and dendritic processes.
Fig. 4.
mRNA expression in PDAPP mice (±SD). There is no
loss of mRNA for neuronal synaptic (synaptophysin, A),
cytoskeletal (MAP-2, B), or metabolic (COX-2,
C; COX-4, D) proteins in 18 month PDAPP heterozygote transgenic mice compared with nontransgenic littermates. In situ hybridization demonstrates significantly
increased GFAP mRNA in heterozygote transgenic mice compared with
nontransgenic littermates at 18 months of age (E)
(p < 0.002 by ANOVA; individual region
t tests not reaching significance), increasing in an
age-related fashion in the heterozygote transgenic mice
(F). dg, Dentate gyrus granule
cell layer; mol, molecular layer of dentate gyrus;
cing, cingulate cortex; erc, entorhinal
cortex; thal, thalamus. +, Post hoc
p < 0.05, 18 versus 4 and 11 months; ++, post hoc
p < 0.0,5 18 versus 4 months.
[View Larger Version of this Image (53K GIF file)]
Neuropil alterations
Finally, we examined whether a glial reaction in the neuropil
occurred consequent to A deposition. GFAP-immunoreactive astrocytes were associated with A deposits and hAPP immunoreactive neurites (Fig. 5). Regional GFAP mRNA message was
increased in the 18-month-old animals compared with 18-month-old
nontransgenic littermates and younger transgenic animals (Fig.
4E,F). GFAP mRNA was increased in parallel
with cortical and hippocampal A deposition and also in the thalamus,
which is devoid of A deposits. GFAP mRNA was not increased in 4- or
11-month-old heterozygote animals compared with nontransgenic
littermates of the same age.
Fig. 5.
Confocal image demonstrating the association of
A deposition (blue) with GFAP-immunoreactive
astrocytes (red) and hAPP immunoreactive structures
(green) consistent with dystrophic neurites in an
18-month-old heterozygote PDAPP transgenic mouse. Scale bar, 25 µm.
[View Larger Version of this Image (178K GIF file)]
DISCUSSION
These results demonstrate that the regional distribution of
amyloid deposition in the PDAPP mice follows an anatomical and topographical hierarchical pattern analogous to that of AD. Cortical areas are affected more than subcortical areas, with deposits in
specific laminar and cytoarchitectural zones, such as the deep layers
of the entorhinal cortex, the molecular layer of CA1, and the outer
molecular layer of the dentate gyrus (Hyman et al., 1986; Arnold et
al., 1991). This exquisite anatomic specificity gives strong
experimental support to the hypothesis that amyloid plaques develop at
sites of axon terminals: (1) superficial layers of the entorhinal
cortex strongly express the transgene and project as the perforant
pathway to the outer molecular layer of the dentate gyrus, the precise
location covered by A deposition (Fig.
6); (2) intrinsic hippocampal connections
from the transgene expressing CA3 pyramidal neurons terminate in the
molecular layer of CA1 and subiculum, which develops early amyloid
deposition; (3) transgene-expressing subicular and CA1 neurons project
to the deep layers of the entorhinal cortex, the latter developing
amyloid plaques despite low trangene expression; and (4) the cortical
afferents projecting to the amyloid laden superficial entorhinal cortex
express the trangene. Thus, A deposits frequently occur in terminal
zones of transgene-positive neurons. However, not all areas receiving
strong projections from hAPP-expressing neurons develop A
deposition. For example, the lateral nucleus of the amygdala, the
thalamic pulvinar, and the pontine nuclei receive prominent cortical
afferents without developing amyloid plaques. Additional studies have
demonstrated that total protein levels of  -secretase-cleaved soluble
hAPP/full-length hAPP in brain homogenates parallels hAPP expression,
but that the conversion of A via the amyloidogenic -secretase
pathway (as measured by APP) is region-specific (Johnson-Wood et
al., 1997). This specificity of APP processing may account, in part, for the distribution of A deposits. Therefore, the level of
transgene expression is unlikely to be the sole factor determining A
deposition, and additional anatomic and metabolic factors play a
role.
Fig. 6.
Immunostaining for A in the hippocampus of an
18-month-old heterozygote transgenic mouse demonstrates the
predisposition for A deposition in the outer molecular layer
(oml) of the dentate gyrus, which is the terminal
zone for the projections of the perforant pathway. Scale bar, 100 µm.
iml, Inner molecular layer; gc, granule cell layer.
[View Larger Version of this Image (51K GIF file)]
The amyloid deposits in the PDAPP mouse are similar to those in AD not
only in regional topography, but also in focal disruption of the
neuropil eliciting a glial and neuritic response (Fig. 5). The age- and
region-dependent rise in GFAP mRNA parallels the association of
reactive astrocytes with extracellular A deposits, providing
additional evidence for A-related degenerative alterations of the
neuropil. Previous studies by Masliah et al. (1996) have demonstrated
that the A deposits in the PDAPP mouse are associated with
dystrophic neurites (immunoreactive for SMI-312, hAPP, synaptophysin, and phosphorylated neurofilaments), although paired helical filaments and neurofibrillary tangles have not been identified. These results imply that A deposition in the neuropil cannot be discounted as
inert, nonspecific, peripheral, or a simple bystander to brain pathological changes.
Our studies also allowed us to test directly the hypothesis that A
deposition is neurotoxic in vivo, in light of convincing in vitro data suggesting acute neurotoxicity of A (Koh et
al., 1990; Mattson et al., 1992; Pike et al., 1993; Cotman et al., 1994; Cotman and Su, 1996; Yankner and Lorenzo, 1996). A injection into the ventricles and brain tissue of animals has been reported to
result in cellular toxicity (Kowall et al., 1991, Emre et al., 1992),
although this is controversial and has not been replicated by others
(Games et al., 1992; Podlisny et al., 1992; Stein-Beherns et al.,
1992). Our results strongly argue against a direct acute neurotoxic
mechanism of A deposits in vivo in the transgenic mouse.
This result is in accord with the lack of correlation between neuronal
loss and amyloid deposition in AD (Wilcock and Esiri, 1982; Braak and
Braak, 1991; Price et al., 1991; Terry et al., 1991; Arriagada et al.,
1992; Hyman et al., 1993; Nagy et al., 1995; Gomez-Isla et al., 1996a).
Nevertheless, the plaque-associated alterations of neuritic and glial
morphology replicates observations in AD that specific subtypes of A
deposits are associated with neurodegenerative changes (Masliah et al.,
1996).
Our methods would not have been sensitive to detect losses confined to
a small subpopulation of neurons or to brain regions other than those
examined. Indeed, degenerative changes such as vacuolization and
cytoplasmic distention have been identified in some layer V neurons of
the frontal cortex of PDAPP mice (Masliah et al., 1996). It remains
possible that older age, or genetic, neuroanatomic, or metabolic
factors absent from this mouse model, may be necessary for progression
from amyloid deposition to generalized neuronal death. Evidence from
Down's syndrome brains suggest that >20 years of exposure to amyloid
deposits in human brain may be required for significant AD changes
(Rumble et al., 1989). Alternatively, overexpression of hAPP may be
neuroprotective in mice, as has been suggested by lesion studies in
hAPP transgenic mice (Mucke et al., 1996). Furthermore, intrinsic
characteristics such as differences in promoter, host strain, hAPP
primary structure, and levels of hAPP expression potentially influence
the phenotype of transgenic mice (Hsiao et al., 1995). Nonetheless, our
data suggest that human APP overexpression and A deposition in the PDAPP mouse produce degenerative changes, including neuritic dystrophy and gliosis, but do not result in overt neuronal loss through 18 months
of age.
FOOTNOTES
Received April 4, 1997; revised June 4, 1997; accepted July 1, 1997.
This work was supported by National Institutes of Health Grant AG05134
and a generous gift of the Walters Family Foundation in the name of
Margaret Siska. We greatly appreciate the helpful comments and
suggestions by Ivan Lieberburg (Athena Neurosciences).
Correspondence should be addressed to Bradley T. Hyman, Alzheimer's
Disease Research Unit, Massachusetts General Hospital, East CNY6320,
149 13th Street, Charlestown, MA 02129.
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