 |
 Previous Article | Next Article 
The Journal of Neuroscience, August 1, 2002, 22(15):6331-6335
BRIEF COMMUNICATION
Reversible Memory Loss in a Mouse Transgenic Model of
Alzheimer's Disease
Linda A.
Kotilinek1,
Brian
Bacskai2,
Marcus
Westerman1,
Takeshi
Kawarabayashi3,
Linda
Younkin3,
Bradley T.
Hyman2,
Steven
Younkin3, and
Karen H.
Ashe1
1 Departments of Neurology and Neuroscience, University
of Minnesota, Minneapolis 55455, 2 Department of Neurology,
Massachusetts General Hospital East, Charlestown, Massachusetts 02129, and 3 Department of Neuroscience, Mayo Clinic,
Jacksonville, Florida 32224
 |
ABSTRACT |
Alzheimer's disease (AD) is a neurodegenerative condition,
believed to be irreversible, characterized by inexorable deterioration of memory and intellect, with neuronal loss accompanying amyloid plaques and neurofibrillary tangles. In an amyloid precursor protein transgenic mouse model, Tg2576, little or no neuronal loss accompanies age-related memory impairment or the accumulation of A , a 40-42 aa
polypeptide found in plaques. Recently, we have shown inverse correlations between brain A and memory in Tg2576 mice stratified by
age (Westerman et al., 2002 ). Broadening the age range examined obscured this relationship, leading us to propose that small, soluble
assemblies of A disrupt cognitive function in these mice. Here we
show that memory loss can be fully reversed in Tg2576 mice using
intraperitoneally administered BAM-10, a monoclonal antibody
recognizing the N terminus of A. The beneficial effect of BAM-10 was
not associated with a significant A reduction, but instead
eliminated the inverse relationship between brain A and memory. We
postulate that BAM-10 acts by neutralizing A assemblies in the brain
that impair cognitive function. Our results indicate that a substantial
portion of memory loss in Tg2576 mice is not permanent. If these A
assemblies contribute significantly to memory loss in AD, then
successfully targeting them might improve memory in some AD patients.
Key words:
Alzheimer's disease; transgenic; behavior; A; monoclonal antibodies; memory
| |
INTRODUCTION |
The Tg2576 transgenic mouse model of
Alzheimer's disease (AD), which overexpresses a mutant form of amyloid
precursor protein (APP), APPK670/671L, linked to
early onset familial AD, develops amyloid plaques and progressive
cognitive deficits (Hsiao et al., 1996). In these mice, A begins to
rise rapidly at ~6 months, coincident with the appearance of
detergent-insoluble A (Kawarabayashi et al., 2001), and memory
ability declines progressively thereafter (Westerman et al., 2002).
Punctate, cored plaques are present in 7- to 8-month-old mice; mature,
diffuse plaques appear at ~12 months of age (Kawarabayashi et al.,
2001). Descriptive characterizations of the relationship between memory
and A in Tg2576 mice (Westerman et al., 2002), along with active
A immunization studies in Tg2576 and other APP transgenic mice
(Janus et al., 2000; Morgan et al., 2000), have demonstrated that A
is necessary and sufficient to disrupt memory and have implicated a
soluble A assembly rather than the accumulation of A or amyloid
plaques per se.
There have been no studies addressing whether the deleterious effects
of A on cognitive function are permanent. Tg2576 mice at 16 months
of age with mature plaque deposition show no neuronal or synaptic loss
(Irizarry et al., 1997), leading us to surmise that cognitive
impairment in these mice might be attributable to neuronal dysfunction
rather than neuronal degeneration. Based on previous studies of the
relationship between A and memory in Tg2576 mice (Westerman et al.,
2002), we hypothesized that if cognitive deficits related to toxic A
assemblies occur primarily in the absence of structural damage, then
passive administration of antibodies to A might rapidly reverse
learning and memory deficits by neutralizing one or more critical A
species, thereby restoring normal cognitive function. To focus our
evaluation on alterations in cognitive function that occur before
plaque deposition, we tested Tg2576 mice at 9-11 months after the
appearance of detergent-insoluble A, but preceding the accumulation
of abundant mature amyloid plaques (Kawarabayashi et al., 2001). At
this age, punctate deposits are present but are rare and difficult to
quantify meaningfully. Because passive immunization affects molecular
targets more rapidly and selectively than active immunization, we chose
passive immunization as a tool to clarify the molecular mechanism by
which memory loss occurs in Tg2576 mice.
| |
MATERIALS AND METHODS |
Mice and behavioral testing. Forty-three female
Tg2576 mice, positive for the HuAPP695.K670N/M671L transgene in
a hybrid C57BL/6/SJL background (Hsiao et al., 1996), were
longitudinally tested twice at 9-11 months of age; a total of 17 Tg2576-positive mice (10 female, 7 male) were longitudinally tested at
2 and 8 months of age, and 10 littermates negative for the transgene (7 female, 3 male) were tested at 3 months of age, in the reference memory version of the Morris water maze (Morris, 1984), as described previously (Westerman et al., 2002).
In the longitudinal experiment involving 9- to 11-month-old mice, a
baseline assessment of the cohort was obtained immediately before
immunization, first in the visible-platform version of the water maze
(3 d, eight trials per day) followed by hidden-platform testing (9 d,
four trials per day). The spatial memory for the platform position was
evaluated in 1 min probe trials administered at the beginning of days
4, 7, and 10 of hidden platform testing. Mice were allocated to the two
treatment groups that were counterbalanced on the basis of the mean of
the three baseline probe scores. All cues were changed, and the
platform position was shifted to the opposite quadrant during
subsequent retesting of immunized mice performed 11-12 d after the
termination of the baseline water maze test. Only a hidden-platform
version of the water maze test was performed. The order of testing mice
from different experimental groups was random, and the experimenters
were unaware of the treatment group. Eight mice that were unable to
learn the visible-platform test or be led out of the pool with an
escape scoop were removed from the experiment, a proportion consistent
with previous studies (Westerman et al., 2002). One mouse died during
baseline testing, before immunization, and another mouse died 1-2 hr
after the final BAM-10 injection, reducing the final control
(IgG) and treatment (BAM-10) group sizes to 17 and 16, respectively.
The latter mouse showed no signs of illness at the time of injection,
making it likely that the acute death was related to a traumatic
injection rather than to encephalitis.
Seventeen naive Tg2576 mice, along with 10 transgene-negative
littermates, were also tested at 2 and 3 months of age, respectively, using the same protocol, except that these mice were prehandled before
testing. Prehandling consisted of performing preparative maneuvers
resembling procedures used during testing 8-10 times during the 2-3
weeks before actual testing. Previous cross-sectional studies of
spatial reference memory during the lifetime of Tg2576 mice in the
C57BL/6/SJL background have shown no differences between Tg2576 mice at
<6 months of age and nontransgenic littermates at <20 months of age
(Westerman et al., 2002). For this reason, we chose to compare Tg2576
mice at 9-11 months of age with younger Tg2576 mice and nontransgenic
littermates. At 8 months of age, the 17 Tg2576 mice were
allocated into two treatment groups counterbalanced on the basis of
mean probe scores at 2 months of age and gender, treated with BAM-10 or
nonspecific IgG, retested in the water maze beginning at 8.3 months of
age, and killed at 8.7 months of age.
Antibody selection and administration. BAM-10 (Sigma, St.
Louis, MO) is a mouse monoclonal antibody recognizing
A(1-12). BAM-10 was chosen on the basis of its ability to bind A
in vivo. Because not all antibodies bind to A in its
native configuration (B. Bacskai and B. T. Hyman, personal
communication), we used multiphoton microscopy, an in vivo
imaging method with ~1 µm resolution, to evaluate the effectiveness
of BAM-10 antibody in living Tg2576 mice. We purified, concentrated,
and labeled BAM-10 with fluorescein, and applied 5-10 µl of a 1 mg/ml solution directly to the cortical surface of 25-month-old Tg2576
mice. We then visualized the fluorescence as described previously
(Bacskai et al., 2001), readily imaging both senile plaques in the
neuropil and amyloid angiopathy in the living mouse brain. The in
vivo immunofluorescent signal colocalized with thioflavine S
staining in cored plaques and in amyloid angiopathy, as well as
revealing nonthioflavine S diffuse deposits (data not shown). Diffuse
but not cored deposits were reduced by 53% after 3 d in
BAM-10-treated mice, an effect similar to that obtained using another
antibody recognizing the N terminus of A, 10D6 (Bacskai et al.,
2001) (data not shown).
Antibodies were administered intraperitoneally beginning 4-5 d after
the last day of baseline water maze pretesting in the longitudinal
experiment involving 9- to 11-month-old mice, and 7 d before water
maze testing in the experiment involving 8-month-old mice. One group of
Tg2576 mice received BAM-10 ascites lacking sodium azide preservative;
the other group if mice received IgG (Sigma). Animals received
0.5 mg of antibody on days 1, 6, and 12 and received 0.25 mg of
antibody on day 4. Mice were killed on the last day of behavioral
testing, 5 d after the last dose.
Serum antibody titers. BAM-10 serum titers were measured
using an adaptation of methods described previously (Schenk et al., 1999). Microtiter ELISA plates (Costar, Cambridge, MA) were coated with
1 µg of aggregated A42 (American Peptide Company, Sunnyvale, CA)
in PBS, pH 8.5, and blocked with 1% BSA (Sigma) in PBS, pH 7.4. Plates
were washed with wash buffer (PBS, 0.05% Tween 20), and threefold
serial dilutions (1:50 to 1:1350) of mouse serum in PBS, 1% BSA,
0.05% Tween 20, and 0.02% sodium azide were incubated overnight at
4°C. Plates were washed and incubated for 1 hr at room temperature in
a 1:10,000 dilution of sheep anti-mouse HRP conjugate (Jackson
ImmunoResearch, West Grove, PA) in PBS, 0.05% Tween, and 0.1% BSA.
Plates were washed and developed with 3,3'5,5' tetramethylbenzidine
(1-Step Slow TMB; Pierce, Rockford, IL). The reaction was stopped with
an equal volume of 1 M
H2SO4, and plates were read
at 450 nm. Optical densities (ODs) of equivalently diluted normal mouse
serum were subtracted from test sera to obtain the net OD. The antibody
titer was defined as the dilution of serum yielding a net OD that was
50% of the maximal signal for that specimen.
A measurements. A was measured by ELISA using the 3160 capture antibody described previously (Kawarabayashi et al., 2001).
| |
RESULTS |
BAM-10 restores spatial learning and memory
We measured spatial reference memory, using the Morris water maze
(Morris, 1984), immediately before and after treatment with BAM-10
(Fig. 1). Training trials were delivered
in blocks of four trials per day, and probe trials were performed on
the mornings after the 12th, 24th, and 36th training trials. When
memory impairment in Tg2576 mice first emerges at 9-11 months of age,
it can be overcome with extensive training, making Tg2576 mice appear
to be comparable with nontransgenic littermates at the end of training (Westerman et al., 2002). The slower rate of learning of Tg2576 mice at
this particular age is easily detectable at the beginning of training,
in the earlier probe scores (Westerman et al., 2002). The first probe
scores were therefore used to assess treatment effects in this
study.
View larger version (18K):
[in this window]
[in a new window]
|
Figure 1.
Longitudinal experimental design using Tg2576 mice
to determine whether memory loss, once present, can be restored.
Spatial reference memory was measured, using the Morris water maze
(Morris, 1984), immediately before and after intraperitoneal
administration of BAM-10, a monoclonal antibody recognizing the N
terminus of A.
|
|
Animals were assigned to BAM-10 or IgG groups after the baseline maze,
counterbalancing for probe scores. The percentage of time spent by mice
in the target quadrant during the baseline test in the BAM-10 and IgG
groups was not significantly different. Mice received three injections
of either 0.5 mg of BAM-10 or nonspecific mouse IgG (days 1, 6, and 12 of the experiment) with a booster of 0.25 mg on day 4. BAM-10 serum
titers, measured using an adaptation of methods described previously
(Schenk et al., 1999), ranged from 1:100 to 1:1100 at 5 d after
the last dose. Performance in the water maze was reassessed beginning
on day 8. The two groups showed significant differences in changes in
performance between baseline and post-treatment tests
[p = 0.03 by t test or by two-way (treatment-by-test session) ANOVA with repeated measures], indicating a significant effect of treatment with BAM-10 (Fig.
2a).
View larger version (22K):
[in this window]
[in a new window]
|
Figure 2.
Spatial reference learning and
memory in 9- to 11-month-old Tg2576 mice before and after treatment
with BAM-10 antibody. The change in retention of spatial memory
occurring as a result of receiving BAM-10 or IgG antibodies
intraperitoneally was measured by subtracting baseline scores from
post-treatment scores to obtain the change in percentage of time spent
in the target quadrant (Change in %-time).
a, Mice 9-11 months of age receiving BAM-10 antibody
showed significantly greater improvement than mice receiving
nonspecific IgG (*p = 0.03 by t
test; IgG, n = 17; BAM-10, n = 16). b, In mice that were impaired at baseline (<40%
of the time spent in the target quadrant), those receiving BAM-10
antibody also showed significantly greater improvement than those
receiving nonspecific IgG (*p = 0.04 by two-way
ANOVA with repeated measures; IgG, n = 13; BAM-10,
n = 14). Post-treatment performance of impaired
mice receiving BAM-10 antibody was significantly higher than baseline
performance (*p = 0.01 by paired t
test) and was similar to that of 2-month-old Tg2576 mice
(n = 17) and 3-month-old nontransgenic littermates
(n = 10). c, BAM-10, but not
nonspecific IgG, restored the retention learning curve of 9- to
11-month-old Tg2576 mice to resemble that of 2-month-old
(Young) Tg2576 mice. d, Acquisition of
spatial reference memory improved in impaired mice receiving BAM-10
antibody, with significantly reduced mean escape latencies on days 3-5
(*p = 0.04 by paired t test), but
not in mice receiving nonspecific IgG. There was a significant
treatment-by-training session (baseline vs post-treatment) interaction
(p = 0.03 by two-way ANOVA with repeated
measures).
|
|
Because not all mice deteriorate at the same rate, a minority of
9- to 11-month-old mice showed superior performance (>40% of time in the target quadrant) comparable with that of the top third of nontransgenic mice. We subsequently segregated the mice on the
basis of baseline scores into impaired (<40% of time in the target
quadrant) and superior (>40% of time in the target quadrant) groups.
To address the question of whether BAM-10 reversed deficits, we
compared the magnitude of the change between baseline and
post-treatment scores in impaired mice only. There was a significant treatment-by-test session (baseline vs post-treatment) interaction in
impaired mice (p = 0.04 by two-way ANOVA with
repeated measures) (Fig. 2b). Post-treatment scores in
impaired mice receiving IgG showed essentially no change relative to
baseline scores. In contrast, impaired mice receiving BAM-10
demonstrated significantly improved scores (p = 0.01 by paired t test) (Fig. 2b). Remarkably,
post-treatment memory ability in BAM-10-treated mice was similar to
that of nontransgenic mice tested at 3 months or transgenic mice tested
at 2 months, before the onset of memory loss (Fig. 2b),
indicating that the memory deficits in 9- to 11-month-old Tg2576 mice
were reversed and memory was fully restored with BAM-10. These results
are supported by comparing the learning curves of retention for BAM-10
and nonspecific IgG treatments in Tg2576 mice (Fig. 2c).
BAM-10 restored the learning curve in 9- to 11-month-old mice to
resemble that of 2-month-old Tg2576 mice.
The restorative effects of BAM-10 were also evident when acquisition of
spatial reference information was examined in impaired mice. We
compared mean escape latencies on days 3-5, because differences in the
performance of Tg2576 mice at this age were most pronounced during this
phase of training, consistent with the maximal sensitivity of the first
probe trial on day 4. There was a significant treatment-by-training session (baseline vs post-treatment) interaction for mean escape latencies (p = 0.03 by two-way ANOVA with
repeated measures). Mean escape latencies measured before and
after IgG administration showed no significant differences [mean
difference, 2.5 sec; 95% confidence interval (CI),  2.8 to 7.8 sec; p = 0.32 by paired t test] (Fig.
2d). In contrast, mean escape latencies after BAM-10 treatment improved significantly (mean difference, 6.3 sec; 95% CI,
0.3 to 12.2 sec; p = 0.04 by paired t
test) (Fig. 2d). We also observed longer escape latencies on
day 1 of the post-treatment test in both groups of mice, suggesting a
retest effect in which mice exhibited retention of spatial information
from the baseline water maze test. The retest effect rapidly
extinguished with retraining in the BAM-10-treated mice but not in the
IgG-treated mice. The beneficial effects of BAM-10 were apparent within
11 d of the first antibody dose, the smallest time interval we
could measure in this study, given the 8 d elapsing between the
first dose and the commencement of retesting in the water maze and the
3 d training interval until the first probe trial.
No significant changes were observed in A levels
After behavioral testing, the brains of 19 IgG-treated mice and 18 BAM-10-treated mice were sequentially extracted
first in Tris-buffered saline (TBS), then in 2% SDS, and finally in
70% formic acid (Kawarabayashi et al., 2001). A40 and A42 were
then analyzed in each fraction by sandwich ELISA. This analysis showed that the improved performance in mice treated with BAM-10 was not
associated with any significant reduction in total A or in A40 or
A42 in any of the fractions analyzed (Fig.
3a). Although BAM-10 was
selected on the basis of its ability to bind to and result in the
disaggregation of diffuse A deposits in Tg2576 mice when very high
concentrations were applied directly to the brain, it is noteworthy
that a similar effect on lowering A in the brain was not apparent in
mice receiving BAM-10 intraperitoneally.
View larger version (26K):
[in this window]
[in a new window]
|
Figure 3.
A levels in Tg2576 mice treated with BAM-10 or
nonspecific IgG antibody. Total A is the sum of A40 and A42 in
TBS, 2% SDS, and formic acid (FA) soluble
fractions measured as described previously (Kawarabayashi et al.,
2001). a, Treatment of mice with BAM-10 was not
associated with a significant reduction in total A or in A40 or
A42 in any of the fractions analyzed (p values
ranged from 0.2 to 0.9). Measurements represent means ± SDs.
Brain A levels were correlated with memory in 8.7-month-old Tg2576
mice treated with BAM-10 or nonspecific IgG antibody. b,
There was a significant inverse correlation between total A and
probe scores in control mice treated with nonspecific IgG.
c, Treatment with BAM-10 eliminated the correlation
between total A and probe scores.
|
|
BAM-10 eliminates the inverse relationship between A
and memory
We have demonstrated previously that there was no obvious
relationship between A and memory in Tg2576 mice unless the mice were stratified by age, whereupon significant inverse correlations emerged (Westerman et al., 2002). Because A rises very rapidly between 8 and 12 months of age (Kawarabayashi et al., 2001), tight stratification by age (in days) is necessary to obtain significant correlations between A and memory during this time. To assess the
effect of BAM-10 on the relationship between A and memory in Tg2576
mice, we measured brain A and post-treatment spatial reference
memory in a second set of mice all exactly 8.7 months of age (all born
within 1 d), treated with either BAM-10 or nonspecific IgG
according to the same schedule as mice in the previously described longitudinal experiment using 9- to 11-month-old mice. As in the previous experiment, treatment with BAM-10 significantly improved memory but had no significant effect on total A or on A40 or A42 in any of the three fractions (data not shown). Analysis of the
first probe scores showed a significant negative correlation (r = 0.88; p = 0.004 by regression
ANOVA) between total A and memory in eight mice treated with
nonspecific IgG (Fig. 3b). A similar negative correlation
was observed in these mice for both A40 and A42 in each of the
three fractions analyzed, with r values ranging from 0.70
to 0.87 and p values ranging from 0.005 to 0.05. Because
the improved spatial learning and memory in mice treated with BAM-10
was not associated with a significant reduction in A, the negative
correlation between A and probe scores was eliminated by BAM-10
treatment. As shown in Figure 3c, there was no significant
correlation between A and probe scores in nine mice treated with
BAM-10 (r = 0.11; p = 0.78 by
regression ANOVA).
Although serum BAM-10 titers showed a 10-fold range in levels, there
was no correlation between peripheral BAM-10 titers and probe scores
(r2 = 0.0002), indicating that
the effect of BAM-10 on memory did not depend on blood levels of the
antibody. These results suggest that BAM-10 enters the CNS and rapidly
neutralizes the deleterious effects of small A assemblies that
interfere with cognitive function, thus restoring normal memory in
Tg2576 mice.
| |
DISCUSSION |
Active immunization with A was first shown to prevent amyloid
deposition (Schenk et al., 1999) and was subsequently shown to prevent
cognitive decline (Janus et al., 2000; Morgan et al., 2000) in two APP
transgenic models of AD. Passive administration of A antibodies
intraperitoneally (Bard et al., 2000) as well as direct application of
A antibodies to the brain (Bacskai et al., 2001) resulted in a
reduction of amyloid burden and A levels and a rapid dispersal of
deposits. None of these studies addressed the question of whether
cognitive deficits, once present, could be restored to normal. Our
results show that A antibodies can indeed reverse behavioral
deficits in a relatively short period of time. Although the IgG-treated
mice performed nearly as well as BAM-10-treated mice after extensive
training (data not shown), this does not diminish the observation that
learning and memory occurred significantly more slowly in the
IgG-treated group.
We postulate that BAM-10, like other A antibodies (Bard et al.,
2000), enters the CNS and acts by neutralizing soluble A assemblies
disrupting cognitive function. These results support the model we
developed to explain the relationship between A and memory in Tg2576
mice (Westerman et al., 2002) (Fig. 4).
Whether the same reversal effect would occur in older Tg2576 mice,
where the presumably small amounts of BAM-10 entering the brain would bind to abundant amyloid deposits and therefore might be less available
to neutralize soluble A assemblies, is unknown. The direct
interaction of BAM-10 with A in the brain is in contrast to the
mechanism of action proposed for m266 which, when chronically administered, lowers brain A levels (DeMattos et al., 2001). It has
been suggested that m266 exerts its action primarily from outside of
the CNS, by creating a peripheral A sink that draws A out of the
brain by mass action (DeMattos et al., 2001). We cannot exclude the
possibility that BAM-10 exerts a similar indirect effect on brain A
in Tg2576 mice. Arguing against this mechanism, however, are the
insignificant changes in brain A after BAM-10 administration that
are in contrast to the dramatic improvement in memory and the absence
of any correlation between serum antibody titers and memory. Whether
m266 and BAM-10 operate at distinct sites is an important question to
resolve, because whether A antibodies act within or outside of the
CNS has important implications for potential inflammatory reactions in
human A immunization studies.
View larger version (17K):
[in this window]
[in a new window]
|
Figure 4.
BAM-10 neutralizes the cognitively disruptive
activity of small A assemblies in the brain. Top,
Memory loss in Tg2576 mice appears to be caused by small A
assemblies (stars) (Westerman et al., 2002) formed
during the conversion of A monomers (circles) to
amyloid deposits (starbursts). Aging refers to the event
or series of events occurring as animals age leading to the initial
aggregation of monomeric A. Little is known about what comprises
these events. Bottom, BAM-10 penetrates into the brain,
where it may bind to these small A assemblies, neutralize their
deleterious effects on cognitive function, and rapidly restore memory
in Tg2576 mice. With prolonged treatment, a reduction in amyloid
deposits may occur.
|
|
The rapid and full restoration of memory suggests that most if not all
of the memory impairment in Tg2576 mice at this age occurs by this
mechanism, and implies that little if any structural damage is
associated with this type of A-mediated brain dysfunction. The
possibility that memory loss in humans might be reversed depends on the
extent to which the same molecular mechanism that disrupts cognitive
function in Tg2576 mice also exists in AD (Klein et al., 2001). Tg2576
mice may represent a model in which memory loss in certain early stages
of AD can be studied. If A species that functionally impair normal
cognition contribute significantly to Alzheimer's dementia, especially
in the early stages, then successfully targeting these species might
improve or restore cognitive function.
Note added in proof. Rapid reversal of memory loss has also
been shown in PDAPP mice receiving passively administered m266 A
antibodies (Dodart et al., 2002), which, together with the findings
reported here, suggests a common mechanism for memory loss in
transgenic APP mice.
| |
FOOTNOTES |
Received April 1, 2002; revised May 10, 2002; accepted May 20, 2002.
This work was supported by National Institutes of Health Grants AG15453
(K.H.A., B.T.H., S.Y.), NS33249 (K.H.A.), MH65465 (K.H.A.), and AG08687
(B.T.H.); by a Pioneer Award from the Alzheimer's Association
(B.T.H.); and by The Walter Family Foundation (B.T.H.). We gratefully
acknowledge Stefanie Schrump, Deirdre Cooper-Blacketer, Jennifer Perry,
Aaron Guimaraes, Jennifer Lang, Jennifer Paulson, and Nardina Nash for
their expertise and dedication testing mice in the water maze. We thank
Megan McLellan and Steve Kajdasz for technical assistance with
immunohistological procedures and Eugene Gnida for technical help
performing ELISAs.
Correspondence should be addressed to Karen H. Ashe, Department of
Neurology, Mayo Mail Code 295, 420 Delaware Street Southeast, Minneapolis, MN 55455. E-mail: hsiao005{at}umn.edu.
T. Kawarabayashi's present address: Department of Neurology, Okayama
University Graduate School of Medicine, Okayama, 700-8558 Japan.
| |
REFERENCES |
-
Bacskai BJ,
Kajdasz ST,
Christie RH,
Carter C,
Games D,
Seubert P,
Schenk D,
Hyman BT
(2001)
Imaging of amyloid- deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy.
Nat Med
7:369-372[Web of Science][Medline].
-
Bard F,
Cannon C,
Barbour R,
Burke RL,
Games D,
Grajeda H,
Guido T,
Hu K,
Huang J,
Johnson-Wood K,
Khan K,
Kholodenko D,
Lee M,
Lieberburg I,
Motter R,
Nguyen M,
Soriano F,
Vasquez N,
Weiss K,
Welch B
(2000)
Peripherally administered antibodies against amyloid -peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease.
Nat Med
6:916-919[Web of Science][Medline].
-
DeMattos RB,
Bales KR,
Cummins DJ,
Dodart JC,
Paul SM,
Holtzman DM
(2001)
Peripheral anti-A antibody alters CNS and plasma A clearance and decreases brain A burden in a mouse model of Alzheimer's disease.
Proc Natl Acad Sci USA
98:8850-8855[Abstract/Free Full Text].
-
Dodart JC,
Bales KR,
Gannon KS,
Greene SJ,
DeMattos RB,
Mathis C,
DeLong CA,
Wu S,
Wu X,
Holtzman DM,
Paul SM
(2002)
Immunization reverses memory deficits without reducing brain Abeta burden in Alzehimer's disease model
Nat Neurosci
5:452-457[Web of Science][Medline].
-
Hsiao K,
Chapman P,
Nilsen S,
Eckman C,
Harigaya Y,
Younkin S,
Yang F,
Cole G
(1996)
Correlative memory deficits, A elevation, and amyloid plaques in transgenic mice.
Science
274:99-102[Abstract/Free Full Text].
-
Irizarry MC,
McNamara M,
Fedorchak K,
Hsiao K,
Hyman BT
(1997)
APPSw transgenic mice develop age-related A deposits and neuropil abnormalities, but no neuronal loss in CA1.
J Neuropathol Exp Neurol
56:965-973[Web of Science][Medline].
-
Janus C,
Pearson J,
McLaurin J,
Mathews PM,
Jiang Y,
Schmidt SD,
Chishti MA,
Horne P,
Heslin D,
French J,
Mount HT,
Nixon RA,
Mercken M,
Bergeron C,
Fraser PE,
St George-Hyslop P,
Westaway D
(2000)
A peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease.
Nature
408:979-982[Medline].
-
Kawarabayashi T,
Younkin LH,
Saido TC,
Shoji M,
Ashe KH,
Younkin SG
(2001)
Age-dependent changes in brain, CSF, and plasma amyloid protein in the Tg2576 transgenic mouse model of Alzheimer's disease.
J Neurosci
21:372-381[Abstract/Free Full Text].
-
Klein WL,
Krafft GA,
Finch CE
(2001)
Targeting small A oligomers: the solution to an Alzheimer's disease conundrum?
Trends Neurosci
24:219-224[Web of Science][Medline].
-
Morgan D,
Diamond DM,
Gottschall PE,
Ugen KE,
Dickey C,
Hardy J,
Duff K,
Jantzen P,
DiCarlo G,
Wilcock D,
Connor K,
Hatcher J,
Hope C,
Gordon M,
Arendash GW
(2000)
A peptide vaccination prevents memory loss in an animal model of Alzheimer's disease.
Nature
408:982-985[Medline].
-
Morris R
(1984)
Developments of a water-maze procedure for studying spatial learning in the rat.
J Neurosci Methods
11:47-60[Web of Science][Medline].
-
Schenk D,
Barbour R,
Dunn W,
Gordon G,
Grajeda H,
Guido T,
Hu K,
Huang J,
Johnson-Wood K,
Khan K,
Kholodenko D,
Lee M,
Liao Z,
Lieberburg I,
Motter R,
Mutter L,
Soriano F,
Shopp G,
Vasquez N,
Vandevert C
(1999)
Immunization with amyloid- attenuates Alzheimer-disease-like pathology in the PDAPP mouse.
Nature
400:173-177[Medline].
-
Westerman M,
Cooper-Blacketer D,
Mariash A,
Kotilinek L,
Kawarabayashi T,
Younkin LH,
Carlson G,
Younkin SG,
Ashe KH
(2002)
The relationship between A and memory in the Tg2576 mouse model of Alzheimer's disease.
J Neurosci
22:1858-1867[Abstract/Free Full Text].
Copyright © 2002 Society for Neuroscience 0270-6474/02/22156331-05$05.00/0
This article has been cited by other articles:
|
|
|
|
 
G. S. Basi, H. Feinberg, F. Oshidari, J. Anderson, R. Barbour, J. Baker, T. A. Comery, L. Diep, D. Gill, K. Johnson-Wood, et al.
Structural Correlates of Antibodies Associated with Acute Reversal of Amyloid {beta}-related Behavioral Deficits in a Mouse Model of Alzheimer Disease
J. Biol. Chem.,
January 29, 2010;
285(5):
3417 - 3427.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. C. Mitchell, B. B. Ariff, D. M. Yates, K.-F. Lau, M. S. Perkinton, B. Rogelj, J. D. Stephenson, C. C.J. Miller, and D. M. McLoughlin
X11{beta} rescues memory and long-term potentiation deficits in Alzheimer's disease APPswe Tg2576 mice
Hum. Mol. Genet.,
December 1, 2009;
18(23):
4492 - 4500.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Yamada, C. Yabuki, P. Seubert, D. Schenk, Y. Hori, S. Ohtsuki, T. Terasaki, T. Hashimoto, and T. Iwatsubo
A{beta} Immunotherapy: Intracerebral Sequestration of A{beta} by an Anti-A{beta} Monoclonal Antibody 266 with High Affinity to Soluble A{beta}
J. Neurosci.,
September 9, 2009;
29(36):
11393 - 11398.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Bach, J.-A. Tschape, F. Kopietz, G. Braun, J. K. Baade, K.-H. Wiederhold, M. Staufenbiel, M. Prinz, T. Deller, U. Kalinke, et al.
Vaccination with A{beta}-Displaying Virus-Like Particles Reduces Soluble and Insoluble Cerebral A{beta} and Lowers Plaque Burden in APP Transgenic Mice
J. Immunol.,
June 15, 2009;
182(12):
7613 - 7624.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. C. Diaz, O. Simakova, K. A. Jacobson, N. Arispe, and H. B. Pollard
From the Cover: Small molecule blockers of the Alzheimer A{beta} calcium channel potently protect neurons from A{beta} cytotoxicity
PNAS,
March 3, 2009;
106(9):
3348 - 3353.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Nishitsuji, T. Tomiyama, K. Ishibashi, K. Ito, R. Teraoka, M. P. Lambert, W. L. Klein, and H. Mori
The E693{Delta} Mutation in Amyloid Precursor Protein Increases Intracellular Accumulation of Amyloid {beta} Oligomers and Causes Endoplasmic Reticulum Stress-Induced Apoptosis in Cultured Cells
Am. J. Pathol.,
March 1, 2009;
174(3):
957 - 969.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Cacucci, M. Yi, T. J. Wills, P. Chapman, and J. O'Keefe
Place cell firing correlates with memory deficits and amyloid plaque burden in Tg2576 Alzheimer mouse model
PNAS,
June 3, 2008;
105(22):
7863 - 7868.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. L. Richard, M. Filali, P. Prefontaine, and S. Rivest
Toll-Like Receptor 2 Acts as a Natural Innate Immune Receptor to Clear Amyloid {beta}1-42 and Delay the Cognitive Decline in a Mouse Model of Alzheimer's Disease
J. Neurosci.,
May 28, 2008;
28(22):
5784 - 5793.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Klyubin, V. Betts, A. T. Welzel, K. Blennow, H. Zetterberg, A. Wallin, C. A. Lemere, W. K. Cullen, Y. Peng, T. Wisniewski, et al.
Amyloid {beta} Protein Dimer-Containing Human CSF Disrupts Synaptic Plasticity: Prevention by Systemic Passive Immunization
J. Neurosci.,
April 16, 2008;
28(16):
4231 - 4237.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Head, V. Pop, V. Vasilevko, M. Hill, T. Saing, F. Sarsoza, M. Nistor, L.-A. Christie, S. Milton, C. Glabe, et al.
A Two-Year Study with Fibrillar {beta}-Amyloid (A{beta}) Immunization in Aged Canines: Effects on Cognitive Function and Brain A{beta}
J. Neurosci.,
April 2, 2008;
28(14):
3555 - 3566.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Yoshihara, S. Takiguchi, A. Kyuno, K. Tanaka, S. Kuba, S. Hashiguchi, Y. Ito, T. Hashimoto, T. Iwatsubo, S. Tsuyama, et al.
Immunoreactivity of Phage Library-derived Human Single-Chain Antibodies to Amyloid Beta Conformers In Vitro
J. Biochem.,
April 1, 2008;
143(4):
475 - 486.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. A. Kotilinek, M. A. Westerman, Q. Wang, K. Panizzon, G. P. Lim, A. Simonyi, S. Lesne, A. Falinska, L. H. Younkin, S. G. Younkin, et al.
Cyclooxygenase-2 inhibition improves amyloid-{beta}-mediated suppression of memory and synaptic plasticity
Brain,
March 1, 2008;
131(3):
651 - 664.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Petratos, Q.-X. Li, A. J. George, X. Hou, M. L. Kerr, S. E. Unabia, I. Hatzinisiriou, D. Maksel, M.-I. Aguilar, and D. H. Small
The -amyloid protein of Alzheimer's disease increases neuronal CRMP-2 phosphorylation by a Rho-GTP mechanism
Brain,
January 1, 2008;
131(1):
90 - 108.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Tampellini, J. Magrane, R. H. Takahashi, F. Li, M. T. Lin, C. G. Almeida, and G. K. Gouras
Internalized Antibodies to the Abeta Domain of APP Reduce Neuronal Abeta and Protect against Synaptic Alterations
J. Biol. Chem.,
June 29, 2007;
282(26):
18895 - 18906.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C.-Y. Lin, T. Gurlo, R. Kayed, A. E. Butler, L. Haataja, C. G. Glabe, and P. C. Butler
Toxic Human Islet Amyloid Polypeptide (h-IAPP) Oligomers Are Intracellular, and Vaccination to Induce Anti-Toxic Oligomer Antibodies Does Not Prevent h-IAPP-Induced {beta}-Cell Apoptosis in h-IAPP Transgenic Mice
Diabetes,
May 1, 2007;
56(5):
1324 - 1332.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Chen, K. S. Chen, D. Kobayashi, R. Barbour, R. Motter, D. Games, S. J. Martin, and R. G. M. Morris
Active {beta}-Amyloid Immunization Restores Spatial Learning in PDAPP Mice Displaying Very Low Levels of {beta}-Amyloid
J. Neurosci.,
March 7, 2007;
27(10):
2654 - 2662.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. M. Prada, M. Garcia-Alloza, R. A. Betensky, S. X. Zhang-Nunes, S. M. Greenberg, B. J. Bacskai, and M. P. Frosch
Antibody-Mediated Clearance of Amyloid-{beta} Peptide from Cerebral Amyloid Angiopathy Revealed by Quantitative In Vivo Imaging
J. Neurosci.,
February 21, 2007;
27(8):
1973 - 1980.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. R. Jack Jr, M. Marjanska, T. M. Wengenack, D. A. Reyes, G. L. Curran, J. Lin, G. M. Preboske, J. F. Poduslo, and M. Garwood
Magnetic Resonance Imaging of Alzheimer's Pathology in the Brains of Living Transgenic Mice: A New Tool in Alzheimer's Disease Research
Neuroscientist,
February 1, 2007;
13(1):
38 - 48.
[Abstract]
[PDF]
|
|
|
|
|
|
|
P. N. Lacor, M. C. Buniel, P. W. Furlow, A. Sanz Clemente, P. T. Velasco, M. Wood, K. L. Viola, and W. L. Klein
A{beta} Oligomer-Induced Aberrations in Synapse Composition, Shape, and Density Provide a Molecular Basis for Loss of Connectivity in Alzheimer's Disease
J. Neurosci.,
January 24, 2007;
27(4):
796 - 807.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. T. Ting, B. G. Kelley, T. J. Lambert, D. G. Cook, and J. M. Sullivan
Amyloid precursor protein overexpression depresses excitatory transmission through both presynaptic and postsynaptic mechanisms
PNAS,
January 2, 2007;
104(1):
353 - 358.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Saganich, B. E. Schroeder, V. Galvan, D. E. Bredesen, E. H. Koo, and S. F. Heinemann
Deficits in Synaptic Transmission and Learning in Amyloid Precursor Protein (APP) Transgenic Mice Require C-Terminal Cleavage of APP
J. Neurosci.,
December 27, 2006;
26(52):
13428 - 13436.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Oddo, V. Vasilevko, A. Caccamo, M. Kitazawa, D. H. Cribbs, and F. M. LaFerla
Reduction of Soluble Abeta and Tau, but Not Soluble Abeta Alone, Ameliorates Cognitive Decline in Transgenic Mice with Plaques and Tangles
J. Biol. Chem.,
December 22, 2006;
281(51):
39413 - 39423.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H.-W. Klafki, M. Staufenbiel, J. Kornhuber, and J. Wiltfang
Therapeutic approaches to Alzheimer's disease
Brain,
November 1, 2006;
129(11):
2840 - 2855.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. L. Patton, W. M. Kalback, C. L. Esh, T. A. Kokjohn, G. D. Van Vickle, D. C. Luehrs, Y.-M. Kuo, J. Lopez, D. Brune, I. Ferrer, et al.
Amyloid-{beta} Peptide Remnants in AN-1792-Immunized Alzheimer's Disease Patients: A Biochemical Analysis
Am. J. Pathol.,
September 1, 2006;
169(3):
1048 - 1063.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. M. Wilcock, J. Alamed, P. E. Gottschall, J. Grimm, A. Rosenthal, J. Pons, V. Ronan, K. Symmonds, M. N. Gordon, and D. Morgan
Deglycosylated anti-amyloid-beta antibodies eliminate cognitive deficits and reduce parenchymal amyloid with minimal vascular consequences in aged amyloid precursor protein transgenic mice.
J. Neurosci.,
May 17, 2006;
26(20):
5340 - 5346.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. B. Lee, L. Z. Leng, B. Zhang, L. Kwong, J. Q. Trojanowski, T. Abel, and V. M.-Y. Lee
Targeting Amyloid-beta Peptide (Abeta) Oligomers by Passive Immunization with a Conformation-selective Monoclonal Antibody Improves Learning and Memory in Abeta Precursor Protein (APP) Transgenic Mice
J. Biol. Chem.,
February 17, 2006;
281(7):
4292 - 4299.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. A. Comery, R. L. Martone, S. Aschmies, K. P. Atchison, G. Diamantidis, X. Gong, H. Zhou, A. F. Kreft, M. N. Pangalos, J. Sonnenberg-Reines, et al.
Acute {gamma}-Secretase Inhibition Improves Contextual Fear Conditioning in the Tg2576 Mouse Model of Alzheimer's Disease
J. Neurosci.,
September 28, 2005;
25(39):
8898 - 8902.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. E. Hartman, Y. Izumi, K. R. Bales, S. M. Paul, D. F. Wozniak, and D. M. Holtzman
Treatment with an Amyloid-{beta} Antibody Ameliorates Plaque Load, Learning Deficits, and Hippocampal Long-Term Potentiation in a Mouse Model of Alzheimer's Disease
J. Neurosci.,
June 29, 2005;
25(26):
6213 - 6220.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. D. Keating
Nanoscience enables ultrasensitive detection of Alzheimer's biomarker
PNAS,
February 15, 2005;
102(7):
2263 - 2264.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Tsuji
DNA Vaccination May Open Up a New Avenue for Treatment of Alzheimer Disease
Arch Neurol,
December 1, 2004;
61(12):
1832 - 1832.
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Qu, R. N. Rosenberg, L. Li, P. J. Boyer, and S. A. Johnston
Gene Vaccination to Bias the Immune Response to Amyloid-{beta} Peptide as Therapy for Alzheimer Disease
Arch Neurol,
December 1, 2004;
61(12):
1859 - 1864.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. N. Lacor, M. C. Buniel, L. Chang, S. J. Fernandez, Y. Gong, K. L. Viola, M. P. Lambert, P. T. Velasco, E. H. Bigio, C. E. Finch, et al.
Synaptic Targeting by Alzheimer's-Related Amyloid {beta} Oligomers
J. Neurosci.,
November 10, 2004;
24(45):
10191 - 10200.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Herrup, R. Neve, S. L. Ackerman, and A. Copani
Divide and Die: Cell Cycle Events as Triggers of Nerve Cell Death
J. Neurosci.,
October 20, 2004;
24(42):
9232 - 9239.
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. S. Gelinas, K. DaSilva, D. Fenili, P. St. George-Hyslop, and J. McLaurin
Immunotherapy for Alzheimer's disease
PNAS,
October 5, 2004;
101(suppl_2):
14657 - 14662.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Krezowski, D. Knudson, C. Ebeling, R. Pitstick, R. K. Giri, D. Schenk, D. Westaway, L. Younkin, S. G. Younkin, K. H. Ashe, et al.
Identification of loci determining susceptibility to the lethal effects of amyloid precursor protein transgene overexpression
Hum. Mol. Genet.,
September 15, 2004;
13(18):
1989 - 1997.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. G. DE FELICE, M. N. N. VIEIRA, L. M. SARAIVA, J. D. FIGUEROA-VILLAR, J. GARCIA-ABREU, R. LIU, L. CHANG, W. L. KLEIN, and S. T. FERREIRA
Targeting the neurotoxic species in Alzheimer's disease: inhibitors of A{beta} oligomerization
FASEB J,
September 1, 2004;
18(12):
1366 - 1372.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. M. Sigurdsson, E. Knudsen, A. Asuni, C. Fitzer-Attas, D. Sage, D. Quartermain, F. Goni, B. Frangione, and T. Wisniewski
An Attenuated Immune Response Is Sufficient to Enhance Cognition in an Alzheimer's Disease Mouse Model Immunized with Amyloid-{beta} Derivatives
J. Neurosci.,
July 14, 2004;
24(28):
6277 - 6282.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. M. Wilcock, A. Rojiani, A. Rosenthal, G. Levkowitz, S. Subbarao, J. Alamed, D. Wilson, N. Wilson, M. J. Freeman, M. N. Gordon, et al.
Passive Amyloid Immunotherapy Clears Amyloid and Transiently Activates Microglia in a Transgenic Mouse Model of Amyloid Deposition
J. Neurosci.,
July 7, 2004;
24(27):
6144 - 6151.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. A. Lemere, A. Beierschmitt, M. Iglesias, E. T. Spooner, J. K. Bloom, J. F. Leverone, J. B. Zheng, T. J. Seabrook, D. Louard, D. Li, et al.
Alzheimer's Disease A{beta} Vaccine Reduces Central Nervous System A{beta} Levels in a Non-Human Primate, the Caribbean Vervet
Am. J. Pathol.,
July 1, 2004;
165(1):
283 - 297.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Das, V. Howard, N. Loosbrock, D. Dickson, M. P. Murphy, and T. E. Golde
Amyloid-{beta} Immunization Effectively Reduces Amyloid Deposition in FcR{gamma}-/- Knock-Out Mice
J. Neurosci.,
September 17, 2003;
23(24):
8532 - 8538.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Gong, L. Chang, K. L. Viola, P. N. Lacor, M. P Lambert, C. E. Finch, G. A. Krafft, and W. L. Klein
Alzheimer's disease-affected brain: Presence of oligomeric A{beta} ligands (ADDLs) suggests a molecular basis for reversible memory loss
PNAS,
September 2, 2003;
100(18):
10417 - 10422.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. V. Terry Jr and J. J. Buccafusco
The Cholinergic Hypothesis of Age and Alzheimer's Disease-Related Cognitive Deficits: Recent Challenges and Their Implications for Novel Drug Development
J. Pharmacol. Exp. Ther.,
September 1, 2003;
306(3):
821 - 827.
[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]
|
|
|
|
|
|
|
D. M. Wilcock, G. DiCarlo, D. Henderson, J. Jackson, K. Clarke, K. E. Ugen, M. N. Gordon, and D. Morgan
Intracranially Administered Anti-Abeta Antibodies Reduce beta -Amyloid Deposition by Mechanisms Both Independent of and Associated with Microglial Activation
J. Neurosci.,
May 1, 2003;
23(9):
3745 - 3751.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. L. Michaelis
Drugs Targeting Alzheimer's Disease: Some Things Old and Some Things New
J. Pharmacol. Exp. Ther.,
March 1, 2003;
304(3):
897 - 904.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
TOP
ABSTRACT
INTRODUCTION
