| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Regular Articles |
4 on the Initial Phase of Amyloid ß-Protein Accumulation in the Human Brain
From the Department of Neuropathology,*
Faculty of
Medicine, University of Tokyo, Tokyo; Core Research for Evolutional
Science and Technology,
Japan Science and
Technology Corporation, Kawaguchi; National Institute of Public
Health,
Tokyo; Gunma University School of
Health Sciences,§
Maebashi; Kyoto Prefectural
University of Medicine, Kyoto; and Gunma Cancer
Center,||
Ohta, Japan
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
4, a strong risk factor for late-onset
Alzheimer’s disease. Using an improved extraction protocol and
specific enzyme-linked immunosorbent assay, we quantified the
levels of Aß40 and Aß42 in the insoluble fractions of brains from
105 autopsy cases, aged 22 to 81 years at death, who
showed no signs of dementia. Aß40 and Aß42 were detected in the
insoluble fractions from all of the brains examined; low levels were
even found in the brains of patients as young as 20 to 30 years of age.
The incidence of significant Aß accumulation increased
age-dependently, with Aß42 levels beginning to rise steeply
in some patients in their late 40’s, accompanied by much
smaller increases in Aß40 levels. The presence of the
apolipoprotein E 4 allele was found to significantly
enhance the accumulation of Aß42 and, to a lesser
extent, that of Aß40. These findings strongly suggest that
the presence of 4 allele results in an earlier onset of Aß42
accumulation in the brain.
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
2,
3, and 4) at a single apoE gene locus on the long arm
of chromosome 19. ApoE3 is the most common and basic form, whereas
apoE2 and apoE4 are relatively minor variants that differ from apoE3 by
a single amino acid substitution. Genetic linkage studies suggest that
the 4 allele is a strong risk factor for late-onset Alzheimer’s
disease (AD), and is associated with an earlier age of
onset.2,3
The potential role of the 4 allele in amyloid
ß-protein (Aß) deposition has thus been of particular interest,
given the critical involvement of Aß in
the pathogenesis of AD.
Most cells, including brain cells, secrete substantial amounts of
Aß40 (the major Aß species, ending at Val40) and Aß42 (a longer,
minor species ending at Ala42) into the extracellular space at a ratio
of 
10 to 1.4
During aging, insoluble amorphous and/or
fibrillar deposits of Aß gradually develop in the extracellular space
of most brains. This Aß deposition is initiated by accumulation of
Aß42,5,6
which is much more amyloidogenic than Aß40.
Indeed, mutations within amyloid precursor protein
(APP) and presenilin 1 and 2,
three genes known to be causatively involved in the development of
familial AD, all induce increased secretion of Aß42.7
Such increased secretion is reasonably postulated to result in
significant Aß42 deposition at a much earlier stage of life,
eventually leading to early-onset familial AD.4
In contrast, the role of the 4 allele in Aß deposition remains an
enigma. Most puzzling are the findings that the 4 allele is
associated with increased numbers of Aß40-positive, but not
Aß42-positive, plaques in sporadic AD brains.8,9
These
findings are substantiated by enzyme-linked immunosorbent assay (ELISA)
showing that 4 allele-positive, sporadic AD brains are characterized
by increased levels of Aß40 but not Aß42.10
This
raises the possibility that the 4 allele is not involved in Aß42
deposition, and suggests that other potential targets of the allele
should be explored. On the other hand, given that Aß42 is by far the
predominant species in the majority of senile plaques, this hypothesis
runs contrary to recent observations that 4 carriers have a greater
number of plaques than noncarriers among unselected autopsy
cases.11-13
We therefore sought to clarify the role of
the 4 allele in the initial phase of Aß40 and Aß42 accumulation
in the human brain using an improved extraction protocol and a
sensitive ELISA.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The present study was based in part on autopsy cases (n = 85; 62 men, 23 women) from the Gunma Cancer Center (Ohta, Gunma, Japan); all of the patients had malignant neoplasms and the ages at death ranged from 25 to 81 years (one at 20 to 29 years, nine at 40 to 49 years, 21 at 50 to 59 years, 25 at 60 to 69 years, 29 at 70 to 81 years; postmortem delay, 1 to 13 hours). The Tokyo Medical Examiner’s Office (Otsuka, Tokyo, Japan)6 was a second source of autopsy cases (n = 20; 16 men, four women), among whom the age at death ranged from 22 to 49 years (four at 20 to 29 years, five at 30 to 39 years, and 11 at 40 to 49 years; postmortem delay, 2 to 24 hours). Cortical blocks were obtained from the prefrontal cortex in each case (Brodmann areas 9 to 11) and stored at -80°C until use. In addition, blocks from adjacent sites and/or from the same locations on the contralateral side were fixed in 10% buffered formalin and processed for histological and immunocytochemical examination.
None of the cases whose brains were analyzed for this study showed any signs of dementia; cases of AD or dementia from other causes were excluded. AD was diagnosed based on both clinical and neuropathological criteria; all cases met the A2 criteria as defined by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association,14 and were classified type C as defined by the Consortium to Establish a Registry for Alzheimer’s Disease.15
Antibodies and Authentic Aß
The monoclonal antibodies against Aß used were BAN50 (raised against Aß1-16), BNT77 (raised against Aß11-28), BA27 (raised against Aß1-40; specific for Aß40), and BC05 (raised against Aß35-43; specific for Aß42).16,17 4G8 (specific for Aß17-24) and 6E10 (raised against Aß1-17) were obtained from Senetek PLC (Maryland Heights, MO).
Synthetic Aß1-40 and Aß1-42 were purchased from Bachem (Torrance, CA). Two species of p3 (Aß17-40 and Aß17-42) were from AnaSpec (San Jose, CA). Aß3(pE)-42 and Aß11(pE)-42 (pE: pyroglutamate) were kindly provided by Dr. T. C. Saido (RIKEN Brain Science Institute, Saitama, Japan).
ELISA
After carefully dissecting out attached leptomeninges and vessels,
each brain tissue sample (120 mg) was homogenized in 4 volumes of
Tris-saline (50 mmol/L Tris-HCl, pH 7.4, 150 mmol/L NaCl) containing 1
mmol/L EGTA, 0.5 mmol/L diisopropyl fluorophosphate, 0.5 mmol/L
phenylmethylsulfonyl fluoride, 1 µg/ml
N
-p-tosyl-L-lysine
chloromethyl ketone, 1 µg/ml antipain, 0.1 µg/ml pepstatin, and 1
µg/ml leupeptin. The homogenate was centrifuged at 540,000 x
g for 20 minutes in a TLX ultracentrifuge (Beckman, Palo
Alto, CA), after which the pellet was washed with the same buffer,
resuspended either by homogenization in 50 volumes of 70% formic
acid18
or by brief sonication in 10 volumes of 6 mol/L
guanidine-HCl in 50 mmol/L Tris-HCl, pH 7.6,19
and
centrifuged once again at 265,000 x g for 20 minutes.
The formic acid supernatant was neutralized with NaOH and Trizma
base,18
whereas the guanidine-HCl supernatant was diluted
at 1:12 to reduce the concentration of guanidine-HCl to 0.5 mol/L. Both
supernatants were then subjected to two-site ELISA as previously
described:6
BNT77 was coated onto a microtiter plate as
the capture antibody, whereas BA27 or BC05 was used as the detection
antibody after conjugation with horseradish peroxidase.
BC05 is known to have a low affinity for Aß43 (1/5 to 1/10 that for
Aß42), but because Aß43 was virtually undetectable in extracts
probed with BC65, a monoclonal anti-Aß43 antibody,18
BC05-based Aß values were considered to reflect Aß42 exclusively.
On the other hand, because BC05 weakly cross-reacts with APP
(1/300 to 1/500 that for Aß42), in cases where the Aß42 levels were
less than 5 pmol/g tissue, it was necessary to correct for APP
binding to accurately assess Aß42 levels.20
As the APP
concentrations in the guanidine-HCl extracts ranged from 8 to 15
nmol/L, the corrected Aß42 levels in these cases were 1/5 of those
presented in Figure 1
.
|
The insoluble pellet in Tris-saline was delipidated with chloroform/methanol (2:1) and then with chloroform/methanol/water (1:2:0.8). The residue was then extracted with formic acid, and the extract was centrifuged. An aliquot of the supernatant was then dried using a Speed Vac (Savant Instruments, Farmingdale, NY) and solubilized with Laemmli sample buffer containing 4 mol/L of urea. The resultant samples were electrophoresed on 16.5% Tris/tricine gels, and the separated proteins were transferred onto nitrocellulose membranes. The blot was then placed in boiled phosphate-buffered saline to enhance the sensitivity,20 and then incubated with BA27, BC05, BAN50, or 6E10. The bound antibodies were detected using either enhanced chemiluminescence or enhanced chemiluminescence plus (Amersham Pharmacia Biotech, Buckinghamshire, UK). Antigen levels in the enhanced chemiluminescence bands of interest were quantified using a model GS-700 imaging densitometer with Molecular Analyst Software (Bio-Rad Laboratories, Hercules, CA).20,21
Immunocytochemistry
Immunocytochemical examination for senile plaques was performed
using 4G8 or Aß polyclonal antibodies as previously
described.6
Detailed description of the immunocytochemical
data will be published elsewhere (Yamaguchi H et al, submitted).
Aß levels in the insoluble fractions were logarithmically related to
the density of the senile plaques, as previously
reported.6
With a single exception, senile plaques were
clearly observed in brains containing more than 100 pmol of Aß42/g
tissue. There was no apparent correlation between amyloid angiopathies
(seen mostly in the leptomeningeal vessels) and levels of either Aß40
or Aß42 in the present autopsy series, which is indicative of the
successful removal of leptomeninges during dissection of the cortex.
ApoE Genotyping
The apoE genotype was determined by polymerase
chain reaction as described previously.22
The frequencies
of the 2, 3, and 4 alleles among the patients were 3.3%,
82.4%, and 14.3%, respectively. These figures are similar to those
reported for the populations of Europe and North America,2
and the frequency of the 4 allele is somewhat higher than that in
the general Japanese population (9%).23,24
Statistical Analysis
Statistical analyses were performed using Microsoft Excel 2000
(Microsoft, Redmond, WA), StatView 4.5 (SAS Institute Inc., Cary, NC),
and SPSS statistics programs (SPSS Inc., Chicago, IL). Aß
levels >5 pmol/g tissue were considered to reflect significant
accumulation, because Aß levels in the majority of patients less than
40 years of age were below this threshold. After subdividing the
patients into seven age groups (20 to 29 years, 30 to 39 years, 40 to
49 years, 50 to 59 years, 60 to 69 years, 70 to 79 years, and >80
years), the incidence of significant Aß accumulation was assessed as
a function of age using the Cochran-Armitage trend test. Respective
levels of the monomeric and dimeric forms of Aß were determined by
quantitative Western blotting. For each protocol the correlation was
evaluated by linear regression analysis. The median ages of the 4
carriers and noncarriers were compared using the Mann-Whitney
U test, and the prevalence of significant accumulation of
Aß in the two groups was compared using Fisher’s exact test. Because
of the small number of patients homozygous for 4 (two patients), the
gene dosage effect of the 4 allele was not investigated. Multiple
linear regression analysis was performed using Aß level as the
dependent variable, and the age at death and the presence of the 4
allele as independent variables. Values of P < 0.05
were considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
We previously showed that Aß could be extracted from the insoluble fraction of nontransfected SH-SY5Y neuroblastoma cells using a guanidine-HCl protocol.20 We also used guanidine-HCl, rather than formic acid, to extract Aß from the insoluble fraction of brains in the present study, because the formic acid protocol requires neutralization with a large volume of alkaline solution, resulting in marked dilution of the protein and a large decrease in the sensitivity of our ELISA.
To test the validity of the protocol, Aß was extracted from the insoluble fractions of many nondemented human brains using either formic acid or guanidine-HCl, and Aß levels in the two groups of extracts were compared. We found that there was a good correlation between Aß levels determined by the two protocols among patients with significant accumulations of Aß [linear regression: y = 0.771x -0.184, r2 = 0.522, P = 0.0001 for Aß40; y = 1.178x -0.576, r2 = 0.796, P < 0.0001 for Aß42, where x = log (Aß levels obtained by the formic acid protocol) and y = log (Aß levels obtained by the guanidine-HCl protocol)]. Interestingly, although formic acid had been believed to be the most effective agent for extracting deposits of fibrillar Aß, guanidine-HCl proved even more effective at extracting low levels of Aß and, importantly, yielded highly reproducible results. As a result, we were able to accurately quantify Aß in the insoluble fractions from all of the brains examined, including those from younger patients, despite the fact that the Aß levels in >60% of the brains were below the detection limit of the formic acid protocol.
Aß Levels in the Insoluble Fraction Increase during Aging
Figure 1
shows Aß levels plotted as a function of the age at
death. Both Aß40 and Aß42 were detected in the insoluble fractions
of the brains of 20- to 30-year-old patients, with levels of the former
being severalfold (more than 10-fold, if corrections were made; see
above and Figure 1
) higher than those of the latter [Aß40, 3
pmol/g tissue; Aß42 (corrected), 0.2 to 0.3 pmol/g tissue]. Aß
levels seemed to be stable during the next 20 years, but then began to
increase exponentially in some patients, beginning at <50 of age
(Figure 1)
. The incidence of significant accumulation of Aß40 or
Aß42 thus increased with age at death (Cochran-Armitage: chi
square = 10.497, P < 0.005 for Aß40; chi
square = 17.863, P < 0.001 for Aß42), as did
the magnitude of the accumulation [linear regression:
y = 0.0116x -0.0012,
r2
= 0.125, P = 0.0002
for Aß40; y = 0.048x -1.835,
r2
= 0.231, P <
0.0001 for Aß42, where x = age and y
= log (Aß levels)]. In addition, there was a close correlation
between the Aß40 and Aß42 levels among individuals [linear
regression: y = 2.291x -0.58,
r2
= 0.569, P <
0.0001, where x = log (Aß40 levels) and
y = log(Aß42 levels)] (Figure 2)
, strongly suggesting that they
increase in a coordinate manner, although the slope of the
age-dependent increases in Aß42 was much steeper than that for Aß40
(P < 0.001). As a result, Aß42 was by far the
predominant species in many brains of elderly patients, with levels
eventually reaching a plateau in patients older than 70 years of age
(Figure 1)
.
|
. Two or three distinct Aß bands
migrating at 3 to 4 kd were labeled with both BA27 and BC05. In terms
of mobility, these bands were very similar to those observed in samples
from elderly patients exhibiting Aß deposition, although the signal
intensity differed greatly. Only the uppermost band at 4 kd was labeled
by BAN50, whereas the upper two bands were labeled with 6E10.
|
6 kd representing a sodium
dodecyl sulfate-stable Aß dimer which was labeled with both BA27 and
BC05 in most cases (Figure 3)
. The dimer band often consisted of
several closely spaced bands that may represent amino-terminally
truncated species. The signal intensity of the Aß dimer occasionally
far exceeded that of the monomer. Although this sodium dodecyl
sulfate-stable Aß dimer could not be quantified by ELISA, previous
Western blot analyses indicate that it seems to accumulate
age-dependently.21
In fact, the levels of the monomeric
and dimeric forms of Aß were well correlated for both Aß40 and
Aß42 [y = 0.791x + 0.248,
r2
= 0.662, P <
0.0001 for Aß40; y = 0.89x + 0.446,
r2
= 0.871, P <
0.0001 for Aß42, where x = log(Aß monomer levels)
and y = log(Aß dimer levels)], indicating that the
accumulation of the dimer was proportional to that of the monomer.
Effect of the 4 Allele on Aß Accumulation
We next examined the effect of 4 allele on the age-dependent
accumulation of Aß (Figure 4)
. Although
there was no significant difference in the ages of 4 carriers and
noncarriers (Mann-Whitney: P = 0.761), the former
accumulated significantly greater amounts of both Aß40 and Aß42
(Fisher’s exact test: P = 0.0048 for Aß40;
P = 0.0005 for Aß42).
|
4 allele on Aß accumulation in more
detail, the patients were subdivided into seven age groups (Figure 4)
.
In patients <40 years old at death (10 cases), levels of both Aß40
and Aß42 were below the 5 pmol/g threshold, irrespective of the
apoE genotype. Between the ages of 40 and 49 years, Aß42
levels in two of seven 4 carriers (28.6%) were above threshold,
whereas they were above threshold in only one of 13 noncarriers (7.7%)
(Figure 4A)
. By 50 years of age and older, most of the 4 carriers
(16 of 18 cases, 88.9%) had accumulated significant levels of Aß42.
In contrast, among noncarriers between 50 and 69 years of age, Aß42
levels remained below 5 pmol/g in most cases (28 of 36 cases, 77.8%),
and even at 70 or more years of age, Aß42 levels in half of the
noncarriers remained below threshold (10 of 21 cases, 47.6%). Multiple
regression analysis showed that Aß42 levels correlated with the
apoE genotype (slope 0.815, t = 3.021,
P = 0.0032) as well as with age at death (slope 0.049,
t = 5.892, P < 0.0001) (r
= 0.529, P < 0.0001). Thus, the 4 allele apparently
enhances age-dependent accumulation of Aß42.
The effect of the 4 allele on Aß40 levels was less remarkable,
although there was a similar tendency toward Aß40 accumulation
(Figure 4B)
. Between the ages of 40 and 59 years, significant
accumulation of Aß40 was detected in five of 11 4 carriers
(45.5%), which was approximately twice the frequency seen among
noncarriers (seven of 30 cases; 23.3%). By 60 years of age and older,
11 of 14 4 carriers (78.6%) showed significant accumulation of
Aß40, whereas only three of 19 noncarriers (15.8%) between the ages
of 60 and 69 years and 10 of 21 at 70 years and older (47.6%) did so.
Thus, Aß40 levels were also related to the apoE genotype
(slope 0.245, t = 2.551, P = 0.0122 for
the presence of 4; slope 0.0119, t = 4.034,
P = 0.0001 for age; r = 0.402,
P < 0.0001), indicating that, as with Aß42,
age-dependent accumulation of Aß40 is enhanced in 4 carriers.
Taken together, out findings strongly suggest that the 4 allele
predisposes the carrier to begin accumulating both Aß42 and Aß40
earlier in life than do noncarriers.
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
90% of Aß40 in
the insoluble fraction remain 24 hours postmortem. In contrast, Aß
levels in the soluble fraction decrease to 50% within 4 hours and
become negligible within 12 hours postmortem.
Our measurements of Aß in the insoluble fraction indicate that,
contrary to earlier ideas, both Aß40 and Aß42 begin to accumulate
at almost the same time and continued to do so in a coordinate manner,
although the former accumulates at a disproportionately slow rate. The
presence of 4 accelerates the initial accumulation of Aß42, and to
a lesser extent, Aß40, which likely explains the association between
the 4 allele and the reduction in the age of onset of
AD.27
From our present data it seems reasonable to assume: 1) that once
Aß42 accumulation is triggered, it continues at a similar rate until
it reaches the plateau; 2) that the effect of the 4 allele is to set
the point at which Aß42 begins to accumulate earlier in life; and 3)
that there is no apparent ceiling for Aß40 accumulation (see Walker
et al13
). The first assumption is consistent with an
earlier immunocytochemical observation that the number of senile
plaques does not continuously increase during the progression of AD,
but seems to level off.28
This suggests a dynamic balance
between Aß deposition and resolution, a hypothesis that was recently
validated by the discovery of the remarkable effect of Aß42
immunization on Aß deposition in PDAPP transgenic
mice.29
The present data also explain why 4 carriers have a greater number
of senile plaques than noncarriers among unselected autopsy
cases,11-13
and if we postulate that AD is the final
consequence of long-term, progressive Aß deposition, they may explain
the aforementioned contradictory observations.8-10
Among
older individuals, in whom Aß42 accumulation has reached a plateau,
there would be no differences in Aß42 deposition between
4-positive and 4-negative AD brains; the only difference would be
the amount of Aß40 deposition (see Figure 4
).8-10
This
may simply mean that the 4-carrying AD patients might have begun
accumulating Aß earlier and thus accumulated more Aß40 than AD
patients not carrying the 4 allele.
Secreted soluble Aß is widely believed to be the source of Aß
deposits in the brain. Aß42 levels in plasma are reported to be
elevated in FAD pedigrees carrying mutant APP or
presenilins,7
but no such observation has been made in
4 carriers. This means that although mutations of the three
causative genes and the presence of 4 allele may all induce
accumulation of Aß to begin decade(s) earlier than it otherwise
would, their respective mechanisms may differ.
Even the brains from young patients contain insoluble Aß, the levels of which are a sensitive indicator of the earliest stage of Aß accumulation. It is therefore possible that these particular insoluble Aß40 and Aß42 species are involved in very earliest stage of Aß accumulation. Insoluble Aß, as defined here, consists of Aß species from both intracellular and extracellular compartments: the aggregated and/or fibrillar Aß in the extracellular space are by far the predominant insoluble species in brains with abundant senile plaques, whereas in brains containing minimal amounts of insoluble Aß42 and no senile plaques, an increase in Aß42 levels is associated with the low-density membrane compartments often referred to as detergent-insoluble, glycolipid-enriched membrane domains (DIGs) (unpublished observations).30 Approximately half of the intracellular insoluble Aß in a human neuroblastoma cell line,20 and presumably in rat brain,31 is localized to this compartment. Thus, one possible pathway leading to Aß accumulation can be traced back to the DIGs within the cells: an abnormal increase in the levels of Aß42 within DIGs may be induced by slowed membrane trafficking associated with aging. It is of note that recent reports32,33 suggest that nonfibrillar Aß42 accumulates intraneuronally in the brains of aged patients not showing signs of dementia, as well as in those with AD and Down’s syndrome patients. Moreover, because caveolae and rafts, representative structures of DIGs, are present mostly in the plasma membrane,30 excess Aß42 accumulating on the plasma membrane would be expected to be shed into the extracellular space and act as a seed for Aß polymerization. This notion is consistent with immunohistochemical and immunoelectron microscopic observations showing Aß to be situated along the plasma membrane in diffuse plaques.34-36
Because apoE plays a major role in the metabolism of
cholesterol,1
which is a major constituent of
DIGs,30
the effect of the 4 allele on Aß accumulation
may reflect alteration of the lipid composition of DIGs. For instance,
a significant decrease in the cholesterol levels is observed in the
brains of 4 knock-in mice.37
Thus, altered cholesterol
metabolism may significantly influence the membrane microenvironment
surrounding Aß and/or APP, leading to aberrant turnover of Aß. The
observation that cholesterol depletion completely inhibits the
generation of Aß suggests this possibility.38
|
Acknowledgements |
|---|
|
Footnotes |
|---|
Supported in part by Research Grants for Longevity Sciences from the Ministry of Health and Welfare, Japan, and from the Sasakawa Health Science Foundation, Japan.
Accepted for publication August 30, 2000.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
4 allele dosage in sporadic Alzheimer’s disease. Brain Res 1997, 748:250-252[Medline]
4 allele in middle-aged non-demented subjects with cerebral amyloid ß protein deposits. Acta Neuropathol (Berl) 1999, 97:82-84[Medline]
4 with late-onset, sporadic Alzheimer’s disease. Ann Neurol 1994, 36:656-659[Medline]
4 and early-onset Alzheimer’s. Nat Genet 1994, 7:10-11[Medline]
This article has been cited by other articles:
 |
|
 |
|
  J. Wu, Md. R. Basha, B. Brock, D. P. Cox, F. Cardozo-Pelaez, C. A. McPherson, J. Harry, D. C. Rice, B. Maloney, D. Chen, et al. Alzheimer's Disease (AD)-Like Pathology in Aged Monkeys after Infantile Exposure to Environmental Metal Lead (Pb): Evidence for a Developmental Origin and Environmental Link for AD J. Neurosci., January 2, 2008; 28(1): 3 - 9. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Zou, H. Yamaguchi, H. Akatsu, T. Sakamoto, M. Ko, K. Mizoguchi, J.-S. Gong, W. Yu, T. Yamamoto, K. Kosaka, et al. Angiotensin-Converting Enzyme Converts Amyloid {beta}-Protein 1 42 (A{beta}1 42) to A{beta}1 40, and Its Inhibition Enhances Brain A{beta} Deposition J. Neurosci., August 8, 2007; 27(32): 8628 - 8635. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-M. Huang, A. Mouri, H. Kokubo, R. Nakajima, T. Suemoto, M. Higuchi, M. Staufenbiel, Y. Noda, H. Yamaguchi, T. Nabeshima, et al. Neprilysin-sensitive Synapse-associated Amyloid-beta Peptide Oligomers Impair Neuronal Plasticity and Cognitive Function J. Biol. Chem., June 30, 2006; 281(26): 17941 - 17951. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.A.R. Martins, A. Oulhaj, C. A. de Jager, and J. H. Williams APOE alleles predict the rate of cognitive decline in Alzheimer disease: A nonlinear model Neurology, December 27, 2005; 65(12): 1888 - 1893. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N Scarmeas, C G Habeck, J Hilton, K E Anderson, J Flynn, A Park, and Y Stern APOE related alterations in cerebral activation even at college age J. Neurol. Neurosurg. Psychiatry, October 1, 2005; 76(10): 1440 - 1444. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. D. Hoyt, P. J. Massman, C. Schatschneider, N. Cooke, and R. S. Doody Individual Growth Curve Analysis of APOE {varepsilon}4-Associated Cognitive Decline in Alzheimer Disease Arch Neurol, March 1, 2005; 62(3): 454 - 459. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Katsuno, M. Morishima-Kawashima, Y. Saito, H. Yamanouchi, S. Ishiura, S. Murayama, and Y. Ihara Independent accumulations of tau and amyloid {beta}-protein in the human entorhinal cortex Neurology, February 22, 2005; 64(4): 687 - 692. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Basha, W. Wei, S. A. Bakheet, N. Benitez, H. K. Siddiqi, Y.-W. Ge, D. K. Lahiri, and N. H. Zawia The Fetal Basis of Amyloidogenesis: Exposure to Lead and Latent Overexpression of Amyloid Precursor Protein and {beta}-Amyloid in the Aging Brain J. Neurosci., January 26, 2005; 25(4): 823 - 829. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Scarmeas, C. Habeck, K. E. Anderson, J. Hilton, D. P. Devanand, G. H. Pelton, M. H. Tabert, J. Flynn, A. Park, A. Ciappa, et al. Altered PET Functional Brain Responses in Cognitively Intact Elderly Persons at Risk for Alzheimer Disease (Carriers of the {epsilon}4 Allele) Am J Geriatr Psychiatry, December 1, 2004; 12(6): 596 - 605. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M. Mann, F. E. Thorngate, Y. Katoh-Fukui, H. Hamanaka, D. L. Williams, S. Fujita, and B. T. Lamb Independent effects of APOE on cholesterol metabolism and brain A{beta} levels in an Alzheimer disease mouse model Hum. Mol. Genet., September 1, 2004; 13(17): 1959 - 1968. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Li, K. Lindholm, L.-B. Yang, X. Yue, M. Citron, R. Yan, T. Beach, L. Sue, M. Sabbagh, H. Cai, et al. Amyloid {beta} peptide load is correlated with increased {beta}-secretase activity in sporadic Alzheimer's disease patients PNAS, March 9, 2004; 101(10): 3632 - 3637. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Scarmeas, C. G. Habeck, Y. Stern, and K. E. Anderson APOE Genotype and Cerebral Blood Flow in Healthy Young Individuals JAMA, September 24, 2003; 290(12): 1581 - 1582. [Full Text] [PDF]
|
|
|
|
|
|
R. Mayeux Apolipoprotein E, Alzheimer Disease, and African Americans Arch Neurol, February 1, 2003; 60(2): 161 - 163. [Full Text] [PDF]
|
|
|
|
 |
|
 N. Oshima, M. Morishima-Kawashima, H. Yamaguchi, M. Yoshimura, S. Sugihara, K. Khan, D. Games, D. Schenk, and Y. Ihara Accumulation of Amyloid {beta}-Protein in the Low-Density Membrane Domain Accurately Reflects the Extent of {beta}-Amyloid Deposition in the Brain Am. J. Pathol., June 1, 2001; 158(6): 2209 - 2218. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
