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(Received for publication, January 10, 1995) From the
Biochemical and immunocytochemical analyses were performed to
evaluate the composition of the amyloid In the brains of patients with Alzheimer's disease (AD), ( Analysis of the SDS-insoluble A
Figure 1:
Analysis of formic acid-extractable
A
Having established the utility of this method,
we used it to analyze the A
The sandwich ELISAs employing BAN-50 for capture do not provide
information on the total A
Figure 2:
A
Direct analysis of the
A Using the BAN-50/BA-27 ELISA
to analyze A
Figure 3:
Immunostaining of AD brain. Similar
regions of adjacent sections from the inferior temporal region of an AD
brain fixed in formalin and photographed at magnification
The immunocytochemical results
shown here and in a recent report by Iwatsubo et al.(21) demonstrate that BC-05 intensely stains all types of
senile plaques, that vessels are stained by both BC-05 and BA-27, and
that BA-27 stains plaques poorly, in many cases only faintly staining
occasional cored plaques (Fig. 3). The apparent paucity of
A Previous
reports (14, 15, 16, 17, 18) have
been confusing as to whether the A Remarkably, the
amount of A
Volume 270,
Number 13,
Issue of March 31, 1995 pp. 7013-7016
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
Protein (A) in Alzheimer
s Disease Brain
BIOCHEMICAL AND IMMUNOCYTOCHEMICAL ANALYSIS WITH ANTIBODIES
SPECIFIC FOR FORMS ENDING AT A
40 OR A42(43) (*)
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
protein (A)
deposited in the brains of patients with Alzheimer's disease
(AD). To quantitate all As present, cerebral cortex was
homogenized in 70% formic acid, and the supernatant was analyzed by
sandwich enzyme-linked immunoabsorbent assays specific for various
forms of A. In 9 of 27 AD brains examined, there was minimal
congophilic angiopathy and virtually all A (96%) ended at
A42(43). The other 18 AD brains contained increasing amounts of
A ending at A40. From this set, 6 brains with substantial
congophilic angiopathy were separately analyzed. In these brains, the
amount of A ending at A42(43) was much the same as in brains
with minimal congophilic angiopathy, but a large amount of A
ending at A40 (76% of total A) was also present.
Immunocytochemical analysis with monoclonal antibodies selective for
As ending at A42(43) or A40 confirmed that, in brains
with minimal congophilic angiopathy, virtually all A is A
ending at A42(43) and showed that this A is deposited in
senile plaques of all types. In the remaining AD brains, A42(43)
was deposited in a similar fashion in plaques, but, in addition, widely
varying amounts of A ending at A40 were deposited, primarily
in blood vessel walls, where some A ending at A42(43) was
also present. These observations indicate that As ending at
A42(43), which are a minor component of the A in human
cerebrospinal fluid and plasma, are critically important in AD where
they deposit selectively in plaques of all kinds.
)amyloid composed of 4-kDa amyloid protein (A)
is deposited in senile plaques and in blood vessel walls.
Immunocytochemical studies using antisera to A have established
that A is deposited not only in neuritic plaques, which are
spherical clusters of altered neurites that in some cases surround well
defined amyloid cores, but also in large numbers of diffuse plaques,
which are poorly circumscribed, immunoreactive lesions showing minimal
neuritic change(1, 2) . Recently, we and others have
shown that normal processing of the large amyloid protein
precursor (-APP) secretes 4-kDa A that is readily detected in
human cerebrospinal fluid and in medium conditioned by cultured
cells(3, 4, 5, 6) . This soluble
4-kDa A is primarily A1-40, although minor amounts of
A1-42 and other species are also
secreted(7, 8, 9) . A1-42 has been
shown to form insoluble amyloid fibrils more rapidly than
A1-40(10, 11, 12, 13) .
Moreover, we have recently used transfected cultured cells to show that
-APP mutations (
I, F) linked to familial AD increase the
percentage of long A1-42(43) secreted(9) . Several
groups have examined the insoluble A that remains after the AD
brain is extracted with high concentrations of
SDS(14, 15, 16, 17, 18) .
Recent reports using this approach, particularly those of Roher and his
colleagues, indicate that the SDS-insoluble amyloid in senile plaque
cores is primarily A1-42(15, 17) , that
diffuse plaques are primarily A17-42(18) , and that
vascular amyloid is a mixture of A1-40 and
A1-42(16) . Thus, the minor, secreted
A1-42 may be critically important in the pathogenesis of AD. in AD brain will substantially
underestimate species ending at A40 if these species are
selectively solubilized in high concentrations of SDS. Thus, to obtain
a better quantitation of the total A in AD brain, we homogenized
AD cerebral cortex directly in 70% formic acid or sequentially
extracted first into Tris-saline buffer and then into formic acid and
analyzed the resultant fractions with sandwich ELISAs that specifically
detect As ending at A40 (A
) or at
A42(43) (A
). To determine where the As
that were quantitated are localized in AD brain, we immunostained
sections with BA-27 and BC-05, the monoclonal antibodies in our
sandwich ELISAs that specifically detect A and
A, respectively.
Tissue Preparation
AD brains were diagnosed on
the basis of classic pathology that included large numbers of senile
plaques. Control brains were plaque-free. In our initial experiments,
cerebral cortex (
0.5 g; at -70 °C) from 3 AD and 3
control brains was Dounce-homogenized (10 strokes) in 4.0 ml of 70%
glass distilled formic acid. After 15 min at 4 °C, homogenates were
centrifuged at 100,000 
g for 1 h. The formic acid
extract (which was between a thin overlying lipid layer and a very
small pellet) was removed and separated into four aliquots, which were
analyzed immediately or completely dried in a rotary vacuum and stored
at 4 °C. The dried aliquots could effectively be resolubilized in
0.2 ml of 70% glass distilled formic acid by sonicating 2 times for 10
s at 50 watts and 70% amplitude (Microsonic Cell Disruptor, Kontes). No
A from the lipid layer or the pellet was detectable as estimated
from 4G8-stained immunoblots. In our second series of experiments, the
A in 27 AD brains and 6 plaque-free control brains was examined by
homogenizing cerebral cortex in Tris-saline buffer containing protease
inhibitors (1 µg/ml pepstatin, 2 µg/ml N
-p-tosyl-L-lysine
chloromethyl ketone, 20 µg/ml aprotinin, 200 µg/ml
phosphoramidon, 2 mM EGTA, and 2 mM phenylmethylsulfonyl fluoride, 2 µg/ml leupeptin) centrifuging
at 100,000 g for 1 h, removing the Tris-saline
supernatant, homogenizing the pellet in 70% formic acid, and
centrifuging again at 100,000 g for 60 min. The
Tris-saline supernatant was diluted 1:4 or 1:40 in buffer EC (0.02 M phosphate, 0.4 M NaCl, 2 mM EDTA, 0.2%
bovine serum albumin, 0.05% CHAPS, and 0.05% NaN
, pH 7).
The formic acid supernatant was diluted 1:40 in 0.25 M Tris
base (pH 8) containing 30% acetonitrile, neutralized with 5 M NaOH, and diluted in buffer EC (1:2.5-1:50). To assess
A recovery, synthetic A (500 pmol of A
plus 500 pmol of A
, Bachem) was added
to samples of cerebral cortex (0.5 g) from control brains prior to
homogenization. This analysis showed that with formic acid extraction
over 93% of the relevant As were recovered when extracts were
directly measured by any of the four sandwich ELISAs employed. In the
more complicated experiments involving Superose 12 chromatography (see
below), recoveries were 50-100%.Sandwich ELISAs for A
Sandwich ELISAs were
performed as described previously(9) . Absorbances falling
within the standard curve for each assay were converted to picomoles,
averaged, corrected when necessary for the recovery observed with that
assay, and expressed as pmol/g wet tissue. The monoclonal antibodies
employed were BAN-50 (anti-A1-16), 4G8
(anti-A17-24)(19) , BA-27, which is specific for
A ending at A40, and BC-05, which is specific for A
ending at A42(43). We have previously shown that BAN-50/BA-27 and
BAN-50/BC-05 ELISAs specifically detect A1-40 and
A1-42 in medium conditioned by transfected cultured
cells(9) . When BAN-50/BC-05 sandwich ELISA is used for
analysis, A1-42 is detected with a sensitivity 10-fold
greater than that for A1-43. When BAN-50/BC-05 assay is used
for analysis, conventional A1-42 (L-aspartate at
A1 and A7) is detected with a sensitivity 20-fold greater
than A1-42 having L-isoaspartate at A1 and
A7 (data not shown).Size Exclusion Chromatography
In some experiments,
the A in supernatants obtained after homogenizing brains in 70%
formic acid as described above was analyzed by Superose 12 (Pharmacia
Biotech Inc.) size exclusion chromatography. An aliquot of each sample
(0.15 ml) was passed through a Superose 12 column (30 300 mm)
running at 0.2 ml/min, and 0.75-ml fractions were collected. Fractions
were completely dried in a rotary vacuum and solubilized in 60%
acetonitrile, 0.2% trifluoroacetic acid by sonicating as above. To
determine where A eluted, 5-µl aliquots from these fractions
were diluted into 100 µl of buffer EC and analyzed by BC-05/4G8 and
BA-27/4G8 sandwich ELISAs. Reactive fractions were pooled, dried in a
rotary vacuum, resolubilized in 1.0 ml of 60% acetonitrile, 0.2%
trifluoroacetic acid as above, diluted (0.2, 0.1, 0.01, or 0.001), and
assayed by BC-05/4G8, BA-27/4G8, BAN-50/BC-05, and BAN-50/BA-27
sandwich ELISAs.Immunocytochemistry
Formalin-fixed,
paraffin-embedded blocks of human inferior temporal cortex were cut at
6 µm. Hydrated sections were treated with 3% hydrogen peroxide to
inactivate endogenous peroxidase activity, and then with 70-99%
formic acid for 5 min to enhance A immunoreactivity. Sections were
incubated with appropriate dilutions of primary antibody for 1 h at
room temperature. Secondary affinity-purified biotinylated goat
anti-mouse IgG (1:200) was applied for 20 min at room temperature, and
tertiary streptavidin-horseradish peroxidase (1:200) was applied for 20
min at room temperature. Sections were washed with 1% normal goat
serum/Tris-buffered saline after each incubation. Peroxidase was
developed with 3,3` diaminobenzidine cosubstrate. Similar results were
obtained using cortical blocks fixed in methacarn (60% methanol, 30%
chloroform, and 10% acetic acid).
Analysis of A
To
quantitate all of the A in Formic Acid Extracts in AD brain quantitatively, we homogenized
AD cerebral cortex directly in 70% formic acid, separated the A in
the formic acid supernatant from larger proteins by gel filtration, and
analyzed the resultant fractions for A using
BA-27(anti-A1-40)/4G8(anti-A17-24) and
BC-05(anti-A35-43)/4G8(anti-A17-24) sandwich
ELISAs that discriminate synthetic A1-40 from
A1-42 (Fig. 1, A and B). To
evaluate the utility of this method, we analyzed 500 pmol of synthetic
A1-40 and A1-42 added to 0.5 g of control
cerebral cortex in 4 ml of 70% formic acid. After homogenization and
Superose 12 chromatography, this synthetic A was readily detected
with recoveries of 50-100% by drying the formic acid fractions,
resolubilizing in 60% acetonitrile plus 0.2% trifluoroacetic acid, and
diluting at least 1:200 prior to sandwich ELISA (Fig. 1, C-F).
in AD and control brain by Superose 12 chromatography. The
results shown here for 1 AD and 1 control brain are typical of 3 AD and
3 control brains analyzed similarly. A, standard curve for
BC-05/4G8 assay. B, standard curve of A for BA-27/4G8
assay. 
, A1-42; 
, A1-40. C,
BC-05/4G8 assay of A in control brain. D, BA-27/4G8 assay
of A in control brain. E, BC-05/4G8 assay of control
brain + synthetic A. F, BA-27/4G8 assay of control
brain + synthetic A. G, BC-05/4G8 assay of AD brain. H, BA-27/4G8 assay of AD brain. Synthetic As (500 pmol of
A1-40 and 500 pmol of A1-42) were added to 70%
formic acid at the same time as the control tissue, which was at
-70 °C. Values for the standard curves represent the mean of
three determinations ± S.E.
in 3 plaque-free control brains and in
3 AD brains with minimal cerebrovascular amyloid. All of the protein
detected by our sandwich ELISAs eluted from the Superose 12 column at
low molecular weight (Fig. 1, G and H) as
previously reported for A analyzed by other
methods(8, 10) . Thus the sandwich ELISAs did not
detect full-length -APP or large -APP fragments containing
internal A domains, as expected from the known specificity of
BC-05 and BA-27 for species that end at A40 or A42(43). Very
little A was detected in plaque-free control brain (Fig. 1, C and D). In the 3 AD brains, the BA-27/4G8 ELISA
showed a total of 93 ± 45 pmol of A/g whereas the BC-05/4G8
ELISA showed 3200 ± 1350 pmol of A/g (Table 1). Thus
97% of the A in these AD brains ended at A42(43). The
A-containing fractions were also analyzed using
BAN-50(anti-A1-16)/BC-05 and BAN-50/BA-27 sandwich ELISAs
that we employed previously(9) . The BAN-50/BA-27 ELISA showed
a total of 73 ± 28 pmol of A/g in AD brain, whereas the
BAN-50/BC-05 ELISA detected 725 ± 347 pmol/g (Table 1).
in AD brain because BAN-50
(anti-A1-16) cannot capture As beginning at or beyond
A17. It was for this reason that we used horseradish
peroxidase-linked 4G8, a monoclonal to A17-24, for detection
in BA-27/4G8 and BC-05/4G8 sandwich ELISAs. The increased amount of
A detected with 4G8 suggests that there may be considerable
amino-terminally truncated A in AD brain, consistent with the
results of others who have examined the SDS-insoluble A in AD
brain(15, 17, 18) . This result should be
interpreted cautiously, however, because other factors such as the
presence of L-isoaspartates at A1 and A7 (15) may account for the diminished signal observed when BAN-50
was used for capture.Analysis of A
Since the ELISAs employed specifically detect the A in 27 AD and 6 Plaque-free Control
Brains
in brain homogenates (Fig. 1), we sequentially extracted samples
of cerebral cortex from 27 AD and 6 control brains first in Tris-saline
containing protease inhibitors and then in 70% formic acid and directly
analyzed the A in the two supernatants after appropriate dilution
and neutralization (see ``Experimental Procedures''). There
was some A in both the Tris-saline and formic acid extracts of the
6 plaque-free control brains analyzed. The amounts present were too
small to quantitate accurately, but the total A present in control
brain was invariably less than 7 pmol/g. Based on this upper limit, the
total A in the 27 AD brains ranged from at least 500 to 4400 times
that in plaque-free control brain. In the AD brains, 98.5% of the total
A present required formic acid for solubilization and only 1.5%
was extracted into Tris-saline. The results of our analysis of the
formic acid supernatants from the 27 AD brains are shown in Table 1and in Fig. 2, where the results of BC-05/4G8 and
BA-27/4G8 analysis have been ordered in terms of increasing BA-27/4G8
signal. In many AD brains, virtually all A was
A, the remaining brains had increasing amounts
of A, and large amounts of A were
deposited in some brains (Fig. 2).
detected by BA-27/4G8 and BC-05/4G8
ELISAs in 27 AD brains. Cases are ordered in terms of increasing
BA-27/4G8 signal.
in 9 brains with minimal congophilic angiopathy (Table 1)
gave results essentially identical to those obtained when A was
first fractionated by Superose 12 chromatography. Virtually all A
in the formic acid extracts from these 9 brains (96%) ended at
A42(43), and substantially more A was detected with BC-05/4G8
(4663 ± 421 pmol/g) than with BAN-50/BC-05 (714 ± 68)
assay. In the formic acid extracts of 6 brains with substantial
congophilic angiopathy (Table 1), A,
analyzed by BC-05/4G8 (5089 ± 409 pmol/g) and BAN-50/BC-05 (826
± 119 pmol/g) ELISA, was found to be present in amounts
essentially identical to those measured in brains with minimal
congophilic angiopathy. In these brains, A, measured
with BA-27/4G8 (13607 ± 3397 pmol/g) and BAN-50/BA-27 (5001
± 2164 pmol/g) ELISAs, was dramatically increased. On average,
67% of the A in brains with substantial congophilic angiopathy
ended at A40, and substantially more A was detected with
BA-27/4G8 than with BAN-50/BA-27 assay indicating that much of the
A ending at A40, like the A ending at A42(43), is
amino-terminally truncated or modified.1-40 extracted into Tris-saline, Suzuki et
al. previously showed a good correlation between the extent of
congophilic angiopathy in AD brain and the amount of A1-40
in the Tris-saline extract(20) . Consistent with this, the
amount of A extracted into Tris-saline was
dramatically increased in brains with substantial as compared to
minimal congophilic angiopathy when measured by either BAN-50/BA-27
(161 ± 60 versus 3 ± 1 pmol/g) or BA-27/4G8 (472
± 103 versus 5 ± 1 pmol/g) assay.Immunocytochemical Analysis
To show unequivocally
that the large amount of A detected by BC-05/4G8 sandwich ELISA is
localized in plaques, we examined AD brains immunocytochemically with
BC-05, 4G8, and BA-27 antibodies, pursuing observations made initially
by Iwatsubo et al.(21) . Both 4G8 and BC-05 intensely
labeled the AD brain, whereas BA-27 showed very little labeling (Fig. 3). 4G8 and BC-05 labeled uncored (diffuse and uncored
neuritic) plaques, the cores of classic neuritic plaques, the region
surrounding plaque cores, and vascular amyloid. BA-27 stained vascular
amyloid quite well but, in contrast to BC-05 and 4G8, stained the cores
of classic neuritic plaques less intensely and almost completely failed
to stain uncored (diffuse and uncored neuritic) plaques or the region
surrounding plaque cores. Essentially identical results were obtained
using sections from tissue fixed in formalin or methacarn (data not
shown). This finding and our observation that, in AD brains with
minimal vascular amyloid, virtually all A ends at A42(43)
provide strong evidence that immunocytochemical analysis with BA-27 and
BC-05 is not distorted by selective destruction of the BA-27 epitope
during tissue fixation or processing.
25
are shown after staining with: A, 4G8 (1:1000), which
recognizes A17-24; B, BA-27 (1:100), which is
specific for As ending at A40; C, BC-05 (1:20,000),
which is specific for As ending at A42(43)(9) . Closedarrows show the cores of classic neuritic
plaques, and openarrows show vessels that are
stained by the antibodies employed. Note the many uncored (diffuse and
uncored neuritic) plaques that are intensely labeled by 4G8 and BC-05
but not BA-27.
in senile plaques is remarkable because
A1-40 is the major A peptide in human cerebrospinal
fluid and it readily forms amyloid fibrils alone or in combination with
A1-42 in vitro. Thus it seemed there might be
selective destruction of the BA-27 epitope during fixation that was
causing misleading immunocytochemical data on the relative amounts of
A and A in plaques and
vessels. To examine this possibility, we focused our initial
biochemical examination of A on cases with minimal congophilic
angiopathy where immunocytochemistry predicted a near absence of
A, and, to be sure that A was not
lost as tissue was processed for biochemistry, we used a procedure that
evaluated the total A in AD brain. Our results show unequivocally
that in brains with minimal congophilic angiopathy virtually all A
ends at A42(43). Thus in many AD brains virtually all A that
is deposited in senile plaques is A. deposited in AD brains is
primarily A or A. Our
analysis of the total A in 27 AD brains showed that in 9 cases,
all with minimal congophilic angiopathy, virtually all A was
A, that the remaining brains had increasing
amounts of A, and that in 6 cases with substantial
congophilic angiopathy A was the major form
deposited. Furthermore, the amount of A in AD brains is at least
500-4400 times that in plaque-free control brains, and less than 2% of
the total A in AD brain is extracted into Tris-saline. This
finding is consistent with previous reports (15, 17, 18) that most of the A in AD
brains is amino-terminally truncated or modified. in AD brains with minimal
congophilic angiopathy and little A was similar to
that in brains with substantial congophilic angiopathy and large
amounts of A. Thus, it appears that deposition of
A in senile plaques is fundamental to AD
pathogenesis with additional deposition of A,
primarily in blood vessel walls, occurring in some cases. This view is
supported by an immunocytochemical study of brains from trisomy 21
patients of various ages that was recently reported by Iwatsubo et
al.(22) . In these brains, A stained by BC-05 was deposited first in diffuse plaques, and
there was essentially no staining by BA-27. Immature neuritic and
mature cored plaques then developed along with congophilic angiopathy.
As this occurred, BC-05 invariably showed intense staining of all
plaques as well as some staining of blood vessel walls whereas BA-27
intensely stained blood vessels and showed increasing staining of
A in plaques, particularly mature cored plaques,
although it never stained plaques to the extent observed with BC-05.
Collectively, the findings reported here, the immunocytochemical data
of Iwatsubo et al.(21, 22) , the recent
analyses showing that most of the A in isolated plaque cores ends
at A42(15, 17) , the demonstration that
A1-42(43) forms fibrils more rapidly than
A1-40(10, 11, 12, 13) ,
and the finding that the familial AD-linked -APP717 mutant
(I, F) increases secretion of A1-42 but not total
4-kDa A (9) indicate that A, which
appears to be a minor component of the A that is normally
secreted, is critically important in AD where it accumulates
selectively in senile plaques of all kinds.
), amyloid protein; -APP,
amyloid protein precursor; ELISA, enzyme-linked immunoabsorbent
assay; CHAPS,
3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate.
We thank C. Cole, Y. E. Dietz, and P. L. Shaffer for
technical assistance.
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
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 K. Iijima, H.-P. Liu, A.-S. Chiang, S. A. Hearn, M. Konsolaki, and Y. Zhong Dissecting the pathological effects of human A{beta}40 and A{beta}42 in Drosophila: A potential model for Alzheimer's disease PNAS, April 27, 2004; 101(17): 6623 - 6628. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Jankowsky, D. J. Fadale, J. Anderson, G. M. Xu, V. Gonzales, N. A. Jenkins, N. G. Copeland, M. K. Lee, L. H. Younkin, S. L. Wagner, et al. Mutant presenilins specifically elevate the levels of the 42 residue {beta}-amyloid peptide in vivo: evidence for augmentation of a 42-specific {gamma} secretase Hum. Mol. Genet., January 15, 2004; 13(2): 159 - 170. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Ertekin-Taner, J. Ronald, H. Asahara, L. Younkin, M. Hella, S. Jain, E. Gnida, S. Younkin, D. Fadale, Y. Ohyagi, et al. Fine mapping of the {alpha}-T catenin gene to a quantitative trait locus on chromosome 10 in late-onset Alzheimer's disease pedigrees Hum. Mol. Genet., December 1, 2003; 12(23): 3133 - 3143. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Dougherty, J. Wu, and R. A. Nichols {beta}-Amyloid Regulation of Presynaptic Nicotinic Receptors in Rat Hippocampus and Neocortex J. Neurosci., July 30, 2003; 23(17): 6740 - 6747. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Xia and M. S. Wolfe Intramembrane proteolysis by presenilin and presenilin-like proteases J. Cell Sci., July 15, 2003; 116(14): 2839 - 2844. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Fukumoto, M. Tennis, J. J. Locascio, B. T. Hyman, J. H. Growdon, and M. C. Irizarry Age but Not Diagnosis Is the Main Predictor of Plasma Amyloid {beta}-Protein Levels Arch Neurol, July 1, 2003; 60(7): 958 - 964. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Bitan, M. D. Kirkitadze, A. Lomakin, S. S. Vollers, G. B. Benedek, and D. B. Teplow Amyloid beta -protein (Abeta ) assembly: Abeta 40 and Abeta 42 oligomerize through distinct pathways PNAS, January 7, 2003; 100(1): 330 - 335. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Selkoe Alzheimer's Disease Is a Synaptic Failure Science, October 25, 2002; 298(5594): 789 - 791. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C. Dimakopoulos and R. J. Mayer Aspects of Neurodegeneration in the Canine Brain J. Nutr., June 1, 2002; 132(6): 1579S - 1582. [Abstract] [Full Text] [PDF]
|
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