 |
 Previous Article | Next Article 
The Journal of Neuroscience, May 15, 2000, 20(10):3606-3611
Evidence for Seeding of  -Amyloid by Intracerebral Infusion of
Alzheimer Brain Extracts in -Amyloid Precursor Protein-Transgenic
Mice
Michael D.
Kane1,
William J.
Lipinski1,
Michael J.
Callahan1,
Feng
Bian1,
Robert A.
Durham1,
Roy D.
Schwarz1,
Alex E.
Roher2, and
Lary C.
Walker1
1 Neuroscience Therapeutics, Parke-Davis Research,
Division of Warner-Lambert, Ann Arbor, Michigan 48105, and
2 Haldeman Laboratory for Alzheimer's Disease Research,
Sun Health Research Institute, Sun City, Arizona 85372
 |
ABSTRACT |
Many neurodegenerative diseases are associated with the abnormal
sequestration of disease-specific proteins in the brain, but the events
that initiate this process remain unclear. To determine whether the
deposition of the  -amyloid peptide (A), a key pathological feature of Alzheimer's disease (AD), can be induced in
vivo, we infused dilute supernatants of autopsy-derived
neocortical homogenates from Alzheimer's patients unilaterally into
the hippocampus and neocortex of 3-month-old -amyloid precursor
protein (APP)-transgenic mice. Up to 4 weeks after the infusion
there was no A-deposition in the brain; however, after 5 months, the
AD-tissue-injected hemisphere of the transgenic mice had developed
profuse A-immunoreactive senile plaques and vascular deposits, some
of which were birefringent with Congo Red. There was limited deposition
of diffuse A also in the brains of APP-transgenic mice infused
with tissue from an age-matched, non-AD brain with mild
-amyloidosis, but none in mice receiving extract from a young
control case. A deposits also were not found in either
vehicle-injected or uninjected transgenic mice or in any nontransgenic
mice. The results show that cerebral -amyloid can be seeded
in vivo by a single inoculation of dilute AD brain
extract, demonstrating a key pathogenic commonality between -amyloidosis and other neurodegenerative diseases involving abnormal protein polymerization. The paradigm can be used to clarify the conditions that initiate in vivo -amyloidogenesis in
the brain and may yield a more authentic animal model of Alzheimer's
disease and other neurodegenerative disorders.
Key words:
Alzheimer's disease; amyloid; angiopathy; A; transgenic; prion; seeding; neurodegeneration; neuroinflammation; animal model; conformational disease
| |
INTRODUCTION |
Similarities in the biophysical
properties of amyloidogenic proteins suggest that diseases
characterized by abnormal protein deposition share certain etiological
mechanisms (Gajdusek, 1994 ; Olafsson et al., 1996; Kisilevsky and
Fraser, 1997; Lansbury, 1997; Price et al., 1998; Prusiner, 1998;
Trojanowski and Lee, 1998; Wakabayashi et al., 1998; Koo et al., 1999;
Vidal et al., 1999). The significance of the protein deposits per se
for the pathogenesis of the diseases is debatable, but the universal
tendency of the offending proteins to self-aggregate suggests that
ordered protein polymerization is important in the pathogenesis of
these disorders. The polymerization of the -amyloid peptide (A)
into senile plaques and cerebrovascular amyloid is a central feature of
cerebral -amyloidoses, such as Alzheimer's disease (AD) (Hardy et
al., 1998; Selkoe, 1999). Although the seeded polymerization of A
can be achieved in vitro (Harper and Lansbury, 1997),
inducing the deposition of A in vivo has been an elusive
goal (Prusiner, 1985; Brown and Gajdusek, 1991). Attempts to produce
AD-like pathology by intracerebral infusion of AD tissues into animals
have produced inconsistent and sometimes paradoxical results (Goudsmit
et al., 1980; Manuelidis and Manuelidis, 1991; Godec et al., 1994).
Marmosets injected with AD brain homogenates developed scattered
deposits of A in the neuroparenchyma and cerebral vasculature 6-7
years after inoculation (Baker et al., 1994). However, the resultant amyloid lesions were not preferentially localized to the injection sites, and the long incubation period limits the utility of the paradigm.
The ordered aggregation of fibrillogenic proteins into amyloid is most
efficient above a critical protein concentration (Harper and Lansbury,
1997). In transgenic mice overexpressing the prion protein (PrP) gene,
the efficiency of prion disease transmission is enhanced by increasing
PrP expression levels (Prusiner et al., 1990). Mice transgenic for the
human -amyloid precursor protein (APP) gene
(Tg[HuAPP695.K670N-M671L]2576) (Hsiao et al., 1996) constitutively
express excess human APP in brain; as they age, the mice sequester
increasing quantities of the amyloidogenic A peptide
intracerebrally, and they begin to develop senile plaques at
approximately the age of 9 months (Hsiao et al., 1997). We therefore
reasoned that APP-transgenic mice would be an advantageous model for
testing the hypothesis that -amyloidosis can be induced by the
intracerebral injection of an appropriate agent. Because the necessary
components of an effective, in vivo A-seeding agent are
unknown, we chose to infuse extracts from AD brains, which unquestionably manifest the necessary conditions for
-amyloidogenesis. Our results show that -amyloid deposition can
be prematurely induced in APP-transgenic mice, but not in
nontransgenic controls, by the intracerebral infusion of dilute AD
brain extract.
Preliminary results from this study were presented at the conference on
Vascular Factors in Alzheimer's Disease, Newcastle, England, May 27, 1999 (Walker et al., 1999).
| |
MATERIALS AND METHODS |
Human tissue extracts. Tissue for preparation of
extracts was derived at autopsy from the superior frontal gyrus or
lateral orbital cortex of four people who had died of confirmed
Alzheimer's disease and from two neurologically normal controls (Table
1). Neuropathological examination
revealed profuse senile plaques and neurofibrillary tangles in the
neocortex and hippocampus of all four Alzheimer's subjects that
fulfilled the Consortium for the Establishment of a Registry for
Alzheimer's Disease (CERAD) criteria for AD. The aged control
case was a nondemented female who died at the age of 77 years of
chronic obstructive pulmonary disease and emphysema.
Neuropathologically, the neocortex contained scattered diffuse,
A-immunoreactive senile plaques; there were no neurofibrillary
tangles in the neocortex or hippocampus, and this person did not
fulfill the CERAD criteria for AD. The young control case was a
25-yr-old male who died of cardiac trauma and who had no AD-like
pathology in the brain.
The tissue samples were fresh-frozen on dry ice and stored at  80°C.
They were homogenized at 10% (w/v) in sterile HBSS, vortexed for 2 min, probe-sonicated for 3 sec, revortexed, and centrifuged at
3000 × g for 5 min to remove tissue debris, including
blood vessels and plaque cores. The supernatant was recovered and
immediately frozen (80°C). The frozen supernatant was then thawed
and further diluted 1:10 (v/v, in HBSS) to a final concentration of 1%
immediately before surgical injection. ELISA of A levels in the
injected material revealed high levels of both A40 and A42 in the
AD cases, intermediate levels in the aged control case, and low or undetectable levels in the young control case (Table 1).
Subjects and experimental design. In the long-term
incubation study (Table 2), 46 3-month-old male mice (34 Tg2576 and 12 nontransgenic littermate
controls) were studied: (1) AD-brain-injected (AD cases 1-4), (2) aged
control brain-injected, (3) young control brain-injected, (4)
vehicle-injected, and (5) untreated. These mice survived for 5 months,
at which age (8 months) amyloid deposition normally is not found in
Tg2576 mice (Hsiao et al., 1997). In the short-term incubation study,
six additional male transgenic mice were injected with brain extract
from AD case 1 to assess the early pathological changes at 5 d, 2 weeks, or 4 weeks after inoculation. Three of the 46 long-term mice and
one short-term animal died during the incubation period (three mice
injected with AD extract and one with aged control extract). These mice were not included in the analysis. All surviving mice were monitored weekly in their cages for signs of behavioral changes. In addition, a
subset of 22 mice representing the long-term treatment groups were
tested for spatial memory in the Morris water maze immediately before
killing.
Stereotaxic surgery. Stereotaxic injections were made under
sodium pentobarbital anesthesia (60 mg/kg, i.p.). Bregma and the skull
surface served as the stereotaxic zero points (Franklin and Paxinos,
1997). The dura mater was surgically exposed, a 27 gauge cannula was
lowered into the right hippocampus [ anterior (A) 2.0, lateral (L)
1.3, ventral (V) 2.2], and 3.5 µl of clear, 1% brain extract or
HBSS was slowly infused (1.0 µl/min) at this site. The cannula was
then raised 1.4 mm (A 2.0, L 1.3, V 0.8), and an additional 1.5 µl of infusate was injected into the overlying neocortex. After the
cortical injection, the cannula was left in place for 2 min before
withdrawal. Postoperatively, the mice were maintained on a warming pad
until they had recovered from the anesthesia, after which they were
returned to their cages. All procedures were conducted in accordance
with institutional guidelines for the care and use of experimental animals.
Histology and quantitation of A deposits. At the age of 8 months (5 months after surgery), the 43 mice remaining in the long-term study were killed under deep sodium pentobarbital anesthesia; the five
AD tissue-injected mice for short-term analysis were similarly killed
at 5 d (n = 1), 2 weeks (n = 2),
and 4 weeks (n = 2) after surgery. Mice were perfused
transcardially with PBS, pH 7.4, followed by phosphate-buffered
4% paraformaldehyde, pH 7.2. The brains were post-fixed in this
solution for 24 hr, then cryoprotected in phosphate-buffered 25%
sucrose, pH 7.4, frozen on dry ice, and coronally sectioned at 20 µm
thickness. Tissue sections were stained immunohistochemically using
primary monoclonal antibodies 6E10 (Senetek, Maryland Heights, MO) to amino acids 5-14 of A; 4G8 (Senetek) to amino acids 17-24 of A;
AT-8 (Polymed, Chicago, IL) to phosphorylated tau; with a monoclonal
antibody to glial fibrillary acidic protein (GFAP; Boehringer Mannheim,
Indianapolis, IN); and with polyclonal antibodies R163 to the
C-terminal 8 amino acids of A40, and R165 to the C-terminal 8 amino
acids of A42 (Pankaj Mehta, Institute for Basic Research in
Developmental Disabilities, Staten Island, NY). Additional sections
were stained with Congo Red and viewed under cross-polarized light, or
with hematoxylin and eosin.
The deposition of A was quantified in the hippocampus at the coronal
level of the injection site by point-counting analysis of the area
occupied by A immunoreactivity (antibodies 6E10 and 4G8) as a
function of the total hippocampal area. Differences in A load were
evaluated statistically by t test or ANOVA with two-tailed significance thresholds.
| |
RESULTS |
Intracerebral injection of brain extract from all four AD cases
into APP-transgenic mice induced the deposition of A peptide in
the ipsilateral hippocampus and (to a lesser degree) neocortex after a
5 month incubation period. A deposits were distributed throughout
the hippocampus, but tended to accumulate preferentially along the
hippocampal fissure, around blood vessels, and beneath pial surfaces
(Figs.
1-4).
Although concentrated most heavily in the injected structures, some
A deposits emerged in regions well beyond the injection sites, even
extending along the corpus callosum and into the contralateral
hemisphere of several mice (Fig. 2). A immunoreactivity in the
noninjected hippocampus was ~10% of that on the injected side, and
this asymmetry was statistically significant
(t(18) = 5.19; p < 0.01).
View larger version (61K):
[in this window]
[in a new window]
|
Figure 1.
Eight-month-old Tg2576 (a)
and nontransgenic (b) mice that had received
equivalent intracerebral injections of dilute AD brain extract (case 1)
5 months earlier. a, A immunoreactivity in the
hippocampus of a transgenic mouse injected with AD brain extract. Note
especially the profuse A deposition along the hippocampal fissure.
b, Absence of A immunoreactivity in a nontransgenic,
littermate control mouse injected with AD brain extract. Antibody 4G8.
Scale bar, 500 µm.
|
|
View larger version (50K):
[in this window]
[in a new window]
|
Figure 2.
Photomontage of a coronal section through the
dorsal forebrain of a transgenic mouse that had been infused
unilaterally (left side) with AD brain extract (AD case
3). A limited amount of A is deposited in and around the corpus
callosum and also in the medial aspect of the contralateral hemisphere.
Arrows mark the hippocampal fissure in each hemisphere.
Antibody R165 to A42. Scale bar, 200 µm.
|
|
View larger version (105K):
[in this window]
[in a new window]
|
Figure 3.
Antibody-antigen adsorption control.
a, A immunoreactivity in the hippocampus of a Tg2576
mouse that had been injected with AD brain extract (AD case 1; antibody
6E10). b, Adjacent control section in which antibody
6E10 was preadsorbed with A1-28 peptide. The
arrowheads denote the same blood vessel that has been
transversely sectioned in a and b. Scale
bar, 100 µm.
|
|
View larger version (62K):
[in this window]
[in a new window]
|
Figure 4.
A immunostaining of the
hippocampus in two Tg2576 mice injected with AD brain extract
(a, b) and in two transgenic mice injected with control
brain extracts (c, d). e shows the amount
of hippocampal A deposition in Tg2576 mice in the four long-term
experimental groups. a, Tg2576 mouse injected with
extract from AD case 1. b, Tg2576 mouse injected with
extract from AD case 2. c, Tg2576 mouse injected with
extract from an aged, non-AD case. d, Tg2576 mouse
injected with extract from a young control case. Antibody 6E10. Scale
bar, 100 µm. e, Mean (± SEM) hippocampal plaque area
occupied by A-immunoreactive deposits in all AD-tissue-injected
Tg2576 mice compared to untreated control transgenic mice (sham and
unoperated), as well as mice infused intracerebrally with young
control and aged control brain extracts. The treatment effect was
statistically significant (F(3,27) = 6.02; p < 0.01). Antibody 4G8 (antibody 6E10
yielded similar results).
|
|
A immunoreactivity was completely blocked by pre-adsorption of
antibody 6E10 with A1-28 peptide (Fig. 3). There was no evidence of
A immunoreactivity in 3- to 4-month-old transgenic mice killed 5 d, 2 weeks, or 4 weeks after AD tissue injection, indicating that the immunoreactivity present at 8 months was not the injectate itself. Neither AD nor control brain extracts produced A deposition in nontransgenic control mice (Fig. 1b), nor were A
deposits seen in the brains of transgenic mice that were uninjected or vehicle-injected. Quantitative analysis confirmed that the
transgenic/AD tissue-injected mice had significantly more A
deposition in the infused hippocampus than did the other groups of
8-month-old transgenic mice (Fig. 4).
Injection of brain extract from a young human resulted in no seeding of
senile plaques or cerebrovascular amyloid in any mice (Fig.
4d). Transgenic mice injected with cerebral tissue extract
from an aged, non-AD case displayed a small amount of A
immunoreactivity in the injected hemisphere (Fig. 4c) with a
distribution similar to that in the AD extract-injected mice, except
that the A accumulation within the brain was only 10-15% of that
seen in AD extract-injected transgenic mice (Fig. 4e).
View larger version (111K):
[in this window]
[in a new window]
|
Figure 5.
Comparative immunostaining of A42
(a) and A40 (b) in a
Tg2576 mouse infused with extract from AD case 3. A40 deposits were
infrequent in AD tissue-infused animals at 8 months of age, and when
they occurred they were usually small, compact parenchymal lesions
(arrowheads) or cerebrovascular deposits. Scale bar, 200 µm.
|
|
In contrast to the deposits that appear normally in Tg2576 mice after 9 months of age, the seeded hippocampal deposits in 8-month-old, AD
extract-injected mice were mostly diffuse in appearance (Figs. 3, 4);
they were strongly immunoreactive with an antibody to A42 (Fig.
5a), infrequently stained with
an antibody to A40 (Fig. 5b), and numerous blood vessels
were affected, especially along the hippocampal fissure (Figs. 3, 4). A
small number of plaques and blood vessels in AD tissue-injected
transgenic mice were birefringent after staining with Congo Red
(Fig. 6); when the same deposits could be identified in
adjacent sections, the congophilic amyloid was usually
A40-immunopositive.
View larger version (190K):
[in this window]
[in a new window]
|
Figure 6.
Congo Red-stained amyloid plaque in the
hippocampus of a Tg2576 mouse infused with extract from AD case 1. Crossed polarizing filters. Scale bar, 10 µm.
|
|
There was no evidence of tau hyperphosphorylation or spongiform change
in any mice; obvious gliosis and neuronal loss were only evident in the
tissue directly damaged by the injection. The mice showed no signs of
motoric or other behavioral dysfunction throughout the postsurgical
incubation period; the performance of extract-injected mice tested in
the water maze did not differ significantly from that of control mice.
Although the injection produced an acute inflammatory reaction directly
after surgery, signs of frank inflammation were minimal at 5 months
after injection.
| |
DISCUSSION |
Our findings show that A deposition can be induced in
APP-transgenic mice by the intracerebral infusion of dilute extracts of human neocortex. Thus, some factors in the human brain promote the
polymerization of A, and our results indicate that the necessary substances are especially plentiful in the Alzheimeric brain. Induction
of A was achieved using tissue from four separate AD cases and was
replicated in a separate experiment using the initial AD case. To
minimize the possibility that the A-immunoreactive material in the
brains of extract-infused Tg2576 mice was introduced in the injectate
itself, the homogenates were centrifuged to remove plaque cores, blood
vessels, and other debris from the supernatant. As a result, there was
no A immunoreactivity in nontransgenic mice injected with human
tissue extract or in transgenic mice 5 d, 2 weeks, or 4 weeks
after injection. The absence of A deposits in the 4 weeks after
infusion indicates that a lag phase precedes the precipitation of A
peptide in the brains of extract-injected transgenic mice.
Under normal circumstances, Tg2576 mice begin to develop -amyloid
deposits at ~9 months of age (Hsiao et al., 1997), so we assessed
A induction between 3 and 8 months of age, before the typical onset
of age-related -amyloidosis. It is significant that we detected A
deposits only in 8-month-old transgenic mice that were injected with
aged human brain extracts and not in age-matched transgenic mice
injected with young brain extract or in untreated transgenic mice. In
addition, A deposits in transgenic mice were 10-fold more abundant
in the injected hippocampus than in the contralateral structure.
Finally, although traumatic brain injury has been shown to acutely
increase cerebral A peptide levels in APP (PDAPP)-transgenic mice
(Smith et al., 1998), our vehicle-injected transgenic mice were devoid
of A immunoreactivity, indicating that surgical trauma alone is
insufficient to induce -amyloidosis in these mice. Interestingly,
the A deposits in extract-injected mice were mostly diffuse,
A42-immunoreactive deposits; typically, before 12 months of age,
Tg2576 mice develop discrete, generally dense deposits, 90% of which
are immunoreactive for both A40 and A42 (Frautschy et al.,
1998).
We speculate that a nucleating seed for the ordered aggregation of A
is abundant in the AD brain, and this seed, in the context of high
levels of endogenous A in APP-transgenic mice, stimulates the
polymerization of the peptide into senile plaques and cerebrovascular amyloid. The nature of the seeding agent remains to be determined, and
it is possible that multiple factors must interact for efficient seeding to occur. Previous studies in rats have demonstrated that intracerebrally injected, purified senile plaque cores tend to be
concentrated at the site of injection or are carried by phagocytic macrophages to the abluminal side of nearby blood vessels (Frautschy et
al., 1992). Perivascular A immunoreactivity was prominent in our
transgenic mice as well, but the great majority of vessels were not
congophilic, and, with only a few exceptions, they contained exclusively A42. Furthermore, in our model, a lag phase precedes A deposition. The chronic infusion of soluble, synthetic A into nontransgenic rodent brains does not result in amyloid deposits similar
to those observed in the AD brain (Frautschy et al., 1996), although
the inclusion of specific cofactors can enhance deposition (Snow et
al., 1994; Frautschy et al., 1996), suggesting that other molecules are
important for the intracerebral generation of fibrillar deposits. The
seeding model will enable the determination of the requisite elements,
including possible molecular chaperones, that initiate A
polymerization in vivo.
A growing body of evidence implicates the aggregation of misfolded
proteins in the pathogenesis of amyloidoses, spongiform encephalopathies, and other neurodegenerative diseases in which protein
accumulation is a common feature (Gajdusek, 1994; Olafsson et al.,
1996; Carrell and Lomas, 1997; Kisilevsky and Fraser, 1997; Lansbury,
1997; Price et al., 1998; Prusiner, 1998; Trojanowski and Lee, 1998;
Wakabayashi et al., 1998; Koo et al., 1999; Vidal et al., 1999). In the
case of -amyloidosis, the highly fibrillogenic A42 may be
culpable (Younkin, 1995; Harper and Lansbury, 1997). If A itself is
the seeding factor in the AD brain fractions, it will be instructive to
establish which species of A is most effective, what cofactors are
required, and whether the AD brain contains a conformational variant of
A that is especially potent at seeding the polymerization of the
endogenous peptide. Injection of synthetic A40 and A42, along
with potential cofactors such as apolipoproteins or extracellular
matrix proteins, could pinpoint the necessary ingredients for optimal
seeding of A, provided that problems of synthetic A batch
variation and peptide aging (Price et al., 1992; Findeis and Molineaux,
1999) can be satisfactorily resolved. Coinjection of synthetic A
with extracts from young brains also would help to establish whether
the necessary chaperones for seeding are present only in the aged
brain. In addition, the possibility that metal ions (Atwood et al.,
1998) may modulate the polymerization of A in vivo
warrants further exploration. The role of apolipoprotein E (ApoE) type
in initiating -amyloid deposition also remains an open question. All
of the AD cases that we studied happened to bear one or more
ApoE 4 alleles, but the two control cases had none. ApoE4
lowers the average age of the onset of -amyloidogenesis in humans
(Walker et al., 2000); further studies are needed to determine why this
is so, and whether ApoE type might affect the ability of AD tissue
extracts to seed amyloidosis in transgenic mice.
In elderly, nondemented humans, diffuse plaques containing only A42
tend to arise, on average, at least a decade before dense-cored plaques
containing A40 emerge (Walker et al., 2000). In contrast, the first
A deposits to appear in normal, aged Tg2576 mice tend to be small,
compact, and immunopositive for both A40 and A42 (Frautschy et
al., 1998). The preponderance of diffuse A42 deposits in
extract-injected APP-transgenic mice suggests that A42 is the
initially seeded form of the peptide and that the addition of A40 to
the lesions is a later event. Thus, APP-transgenic mice infused
intracerebrally with AD tissue may model more faithfully the early
stages of amyloid deposition in humans than do normal, aged Tg2576
mice. It will be informative to assess the evolution of seeded A
deposits in APP-transgenic mice as the animals progress beyond 8 months of age. Human brain extracts might also be used to seed protein
deposition in animal models of other neurodegenerative disorders, for
example in accelerating tauopathy in tau-transgenic mice (Ishihara et
al., 1999).
Although there is little indication of chronic inflammation in the
injected mice, the participation of an infectious microorganism in
promoting the amyloidosis cannot yet be definitively ruled out.
Furthermore, aside from amyloid deposition, the injected mice did not
develop other hallmarks of AD, such as neurofibrillary tangles or
neuronal loss, during the 5 month incubation period studied. However,
demonstration that -amyloid formation can be induced in
APP-transgenic mice may help to illuminate the early stages of
cerebral -amyloidogenesis and could furnish clues to the
pathogenesis of AD and other diseases involving abnormal protein polymerization.
| |
FOOTNOTES |
Received Dec. 23, 1999; revised Feb. 16, 2000; accepted Feb. 29, 2000.
We gratefully acknowledge the recommendations of Drs. Byron Caughey and
Richard Race (National Institute of Allergy and Infectious Diseases) on
the brain extract-preparation methods and the helpful comments of Drs.
Mathias Jucker and Scott Baron.
Correspondence should be addressed to Lary C. Walker, Neuroscience
Therapeutics, Parke-Davis Pharmaceutical Research, Division of
Warner-Lambert, 2800 Plymouth Road, Ann Arbor, MI 48105. E-mail: lary.walker{at}wl.com.
| |
REFERENCES |
-
Atwood CS,
Moir RD,
Huang X,
Scarpa RC,
Bacarra NME,
Romano DM,
Hartshorn MA,
Tanzi RE,
Bush AI
(1998)
Dramatic aggregation of Alzheimer A by Cu(II) is induced by conditions representing physiological acidosis.
J Biol Chem
273:12817-12826[Abstract/Free Full Text].
-
Baker HF,
Ridley RM,
Duchen LW,
Crow TJ,
Bruton CJ
(1994)
Induction of (A4)-amyloid in primates by injection of Alzheimer's disease brain homogenate.
Mol Neurobiol
8:25-39[Web of Science][Medline].
-
Brown P,
Gajdusek DC
(1991)
The human spongiform encephalopathies: Kuru, Creutzfeld-Jakob disease, and the Gerstmann-Straussler-Scheinker syndrome.
Curr Top Microbiol Immunol
172:1-20[Medline].
-
Carrell RW,
Lomas DA
(1997)
Conformational disease.
Lancet
350:134-138[Web of Science][Medline].
-
Findeis MA,
Molineaux SM
(1999)
Design and testing of inhibitors of fibril formation.
Methods Enzymol
309:476-488[Web of Science][Medline].
-
Franklin KBJ,
Paxinos G
(1997)
In: The mouse brain in stereotaxic coordinates. San Diego: Academic.
-
Frautschy SA,
Cole GM,
Baird A
(1992)
Phagocytosis and deposition of vascular -amyloid in rat brains injected with Alzheimer -amyloid.
Am J Pathol
140:1389-1399[Abstract].
-
Frautschy SA,
Yang F,
Calderon L,
Cole GM
(1996)
Rodent models of Alzheimer's disease: Rat A infusion approaches to amyloid deposits.
Neurobiol Aging
17:311-321[Web of Science][Medline].
-
Frautschy SA,
Yang F,
Irrizarry M,
Hyman B,
Saido TC,
Hsiao K,
Cole GM
(1998)
Microglial response to amyloid plaques in APPsw transgenic mice.
Am J Pathol
152:307-317[Abstract].
-
Gajdusek DC
(1994)
Spontaneous generation of infectious nucleating amyloids in the transmissible and nontransmissible cerebral amyloidoses.
Mol Neurobiol
8:1-13[Web of Science][Medline].
-
Godec MS,
Asher DM,
Kozachuk WE,
Masters CL,
Rubi JU,
Payne JA,
Rubi-Villa DJ,
Wagner EE,
Rapoport SI,
Schapiro MB
(1994)
Blood buffy coat from Alzheimer's disease patients and their relatives does not transmit spongiform encephalopathy to hamsters.
Neurology
44:1111-1115[Abstract/Free Full Text].
-
Goudsmit J,
Morrow CH,
Asher DM,
Yanagihara RT,
Masters CL,
Gibbs CJ,
Gajdusek Jr DC
(1980)
Evidence for and against the transmissibility of Alzheimer's disease.
Neurology
30:945-950[Abstract/Free Full Text].
-
Hardy J,
Duff K,
Gwinn Hardy K,
Perez-Tur J,
Hutton M
(1998)
Genetic dissection of Alzheimer's disease and related dementias: amyloid and its relationship to tau.
Nat Neurosci
1:355-358[Web of Science][Medline].
-
Harper JD,
Lansbury PT
(1997)
Models of amyloid seeding in Alzheimer's disease and scrapie: mechanistic truths and physiological consequences of the time-dependent solubility of amyloid proteins.
Annu Rev Biochem
66:385-407[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].
-
Hsiao K,
Pogemiller L,
Clark HB
(1997)
Age-related neuropathology in transgenic mice with human mutant APP.
Soc Neurosci Abstr
23:1647.
-
Ishihara T,
Hong M,
Zhang B,
Nakagawa Y,
Lee MK,
Trojanowski JQ,
Lee VM-Y
(1999)
Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform.
Neuron
24:751-762[Web of Science][Medline].
-
Kisilevsky R,
Fraser PE
(1997)
A amyloidogenesis: unique, or variation on a systemic theme?
Crit Rev Biochem Mol Biol
32:361-404[Web of Science][Medline].
-
Koo EH,
Lansbury PT,
Kelly JW
(1999)
Amyloid diseases: abnormal protein aggregation in neurodegeneration.
Proc Natl Acad Sci USA
96:9989-9990[Free Full Text].
-
Lansbury PT
(1997)
Structural neurology: are seeds at the root of neuronal degeneration?
Neuron
19:1151-1154[Web of Science][Medline].
-
Manuelidis EE,
Manuelidis L
(1991)
Search for transmissible agent in Alzheimer's disease: studies of human buffy coat.
Curr Top Microbiol Immunol
172:275-280[Medline].
-
Olafsson I,
Thorsteinsson O,
Jensson O
(1996)
The molecular pathology of hereditary cystatin C amyloid angiopathy causing brain hemorrhage.
Brain Pathol
6:121-126[Web of Science][Medline].
-
Price DL,
Borchelt DR,
Walker LC,
Sisodia SS
(1992)
Toxicity of synthetic A peptides and modeling of Alzheimer's disease.
Neurobiol Aging
13:623-625[Web of Science][Medline].
-
Price DL,
Sisodia SS,
Borchelt DR
(1998)
Genetic neurodegenerative diseases: The human illness and transgenic models.
Science
282:1079-1083[Abstract/Free Full Text].
-
Prusiner SB
(1985)
Scrapie prions, brain amyloid, and senile dementia.
Curr Top Cell Regul
26:79-95[Web of Science][Medline].
-
Prusiner SB
(1998)
Prions.
Proc Natl Acad Sci USA
95:13363-13383[Abstract/Free Full Text].
-
Prusiner SB,
Scott M,
Foster D,
Pan KM,
Groth D,
Mirenda C,
Torchia M,
Yang SL,
Serban D,
Carlson GA,
Hoppe PC,
Westaway D,
DeArmond SJ
(1990)
Transgenetic studies implicate interactions between homologous PrP isoforms in scrapie prion replication.
Cell
63:673-686[Web of Science][Medline].
-
Selkoe DJ
(1999)
Biology of -amyloid precursor protein and the mechanism of Alzheimer's disease.
In: Alzheimer disease, Ed 2 (Terry RD,
Katzman R,
Bick KL,
Sisodia SS,
eds), pp 293-310. Philadelphia: Lippincott Williams and Wilkins.
-
Smith DH,
Nakamura M,
McIntosh TK,
Wang J,
Rodriguez A,
Chen XH,
Raghupathi R,
Saatman KE,
Clemens J,
Schmidt ML,
Lee VM,
Trojanowski JQ
(1998)
Brain trauma induces massive hippocampal neuron death linked to a surge in -amyloid levels in mice overexpressing mutant amyloid precursor protein.
Am J Pathol
153:1005-1010[Abstract/Free Full Text].
-
Snow AD,
Sekiguchi R,
Nochlin D,
Fraser P,
Kimata K,
Mizutani A,
Arai M,
Schreier WA,
Morgan DG
(1994)
An important role of heparan sulfate proteoglycan (perlecan) in a model system for the deposition and persistence of fibrillar A-amyloid in rat brain.
Neuron
12:219-234[Web of Science][Medline].
-
Trojanowski JQ,
Lee VM-Y
(1998)
Aggregation of neurofilament and
 -synuclein proteins in Lewy bodies.
Arch Neurol
55:151-152[Free Full Text]. -
Vidal R,
Frangione B,
Rostagno A,
Mead S,
Revesz T,
Plant G,
Ghiso J
(1999)
A stop-codon mutation in the BRI gene associated with familial British dementia.
Nature
399:776-781[Medline].
-
Wakabayashi K,
Hayashi S,
Kakita A,
Yamada M,
Toyoshima Y,
Yoshimoto M,
Takahashi H
(1998)
Accumulation of -synuclein/NACP is a cytopathological feature common to Lewy body disease and multiple system atrophy.
Acta Neuropathol (Berl)
96:445-452[Medline].
-
Walker LC,
Lipinski WJ,
Callahan MJ,
Bian F,
Durham RA,
Schwarz RD,
Roher AE,
Kane MD
(1999)
Induction of -amyloidosis in APP-transgenic mice by the intracerebral injection of Alzheimer brain homogenate.
Alzheimer's Reports
2:541.
-
Walker LC, Pahnke J, Madauss M, Vogelgesang S, Pahnke A, Herbst EW,
Stausske D, Walther R, Kessler C, Warzok
RW (2000) Apolipoprotein E4 promotes the early deposition of
A42 and then A40 in the elderly. Acta Neuropathol (Berl), in
press.
-
Younkin SG
(1995)
Evidence that A42 is the real culprit in Alzheimer's disease.
Ann Neurol
37:287-288[Web of Science][Medline].
Copyright © 2000 Society for Neuroscience 0270-6474/00/20103606-06$05.00/0
This article has been cited by other articles:
|
|
|
|
 
Y. S. Eisele, T. Bolmont, M. Heikenwalder, F. Langer, L. H. Jacobson, Z.-X. Yan, K. Roth, A. Aguzzi, M. Staufenbiel, L. C. Walker, et al.
Induction of cerebral {beta}-amyloidosis: Intracerebral versus systemic A{beta} inoculation
PNAS,
August 4, 2009;
106(31):
12926 - 12931.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Soto and L. D. Estrada
Protein Misfolding and Neurodegeneration
Arch Neurol,
February 1, 2008;
65(2):
184 - 189.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Meyer-Luehmann, J. Coomaraswamy, T. Bolmont, S. Kaeser, C. Schaefer, E. Kilger, A. Neuenschwander, D. Abramowski, P. Frey, A. L. Jaton, et al.
Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host.
Science,
September 22, 2006;
313(5794):
1781 - 1784.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. M. Robbins, R. A. Betensky, S. B. Domnitz, S. M. Purcell, M. Garcia-Alloza, C. Greenberg, G. W. Rebeck, B. T. Hyman, S. M. Greenberg, M. P. Frosch, et al.
Kinetics of Cerebral Amyloid Angiopathy Progression in a Transgenic Mouse Model of Alzheimer Disease
J. Neurosci.,
January 11, 2006;
26(2):
365 - 371.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. H. Mohajeri, M. A. Wollmer, and R. M. Nitsch
Abeta 42-induced Increase in Neprilysin Is Associated with Prevention of Amyloid Plaque Formation in Vivo
J. Biol. Chem.,
September 13, 2002;
277(38):
35460 - 35465.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
TOP
ABSTRACT
INTRODUCTION
