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Amyloid (A) deposition in chromosome 1Цlinked Alzheimer's disease The volga german families.

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Amyloid (Ap) Deposition in
Chromosome 1-linked Alzheimer's Disease:
"he Volga German F d e s
D. M. A. Mann,* T. Iwatsubo,t D. Nochlin,+ S. M. Sumi,$ E. Levy-Lahad,$ and T. D. Bird"
Amyloid P protein (AD) deposition was investigated in the frontal cortex of 6 cases of (genetically confirmed) chromosome 1-linked Alzheimer's disease (AD)(PS-2 gene mutation) among the Volga German families using the end-specific
monoclonal antibodies BA27 and BC05 to detect the presence of A&, and Af342(43),
respectively. In all patients,
was the predominant peptide species present, although the total amount of
and AP42(43) deposited in plaques did
not differ from that seen in sporadic AD and was significantly lower than that occurring in AD due to PS-1 gene
mutations. Therefore, mutations in the PS-2 gene, like those in the presenilin-1 (PS-1) and amyloid precursor protein
(APP) genes, are associated with an initial and preferential deposition of AP42(43)
within the brain. Although the mechanisms(s) whereby the PS-1 and PS-2 gene mutations operate remains unclear, it seems from the present study that the
effect of the PS-2 gene mutation on the brain is much less severe, at least as far as AP deposition is concerned, than
that of the PS-1 mutation, which seems to confer a much earlier and a much more aggressive development of AD.
Mann DMA, Iwatsubo T, Nochlin D, Sumi SM, Levy-Lahad E, Bird TD. Amyloid (AP) deposition in
chromosome 1-linked Alzheimer's disease: the Volga German families. Ann Neurol 1997;41:52-57
Alzheimer's disease (AD) affects mostly elderly persons,
although in some individuals the disorder appears to
be inherited in an autosomally dominant fashion with
disease onset occurring usually before or during the
sixth decade of life. In some such persons missense mutations in a gene on chromosome 21 encoding the amyloid precursor protein (APP) segregate with the disease and seem causal [ I , 21. In others, where disease
onset is often well before 50 years of age, mutations
in a gene (termed presenilin-1 [PS-11) located on chromosome 14 appear to be responsible [3-111. A third
autosomal dominant locus, responsible for AD among
the so-called Volga German families, occurs on chromosome 1 [12] and produces a missense mutation at
codon 141 (Ni4'I)in a gene termed presenilin-2 (PS2) [4,13, 141. A further mutation (M'"V) in this same
gene has recently been reported in an Italian family
with AD [14].
The precise mechanism(s) by which these genetic
defects operate to produce the pathological phenotype
of AD is not known. However, there is evidence
from in vitro studies [15-171 that (one of) the effects
of the APP717[15] and PS-1 [16, 171 gene mutations
may be to favor the production of the more highly
or
aggregable [ 181 form of amyloid p protein, AP42(43j
long AP. The exaggerated deposition of this within
plaques in the brains of patients bearing these mutations [19-221 would be consistent with such a mechanism. The PS-2 gene on chromosome 1 bears strong
homology to the PS-1 gene on chromosome 14 [4,13,
141 and both may encode proteins that serve a similar
or related function. Hence, it is possible that the PS-2
mutation on chromosome 1 within the Volga German
families also influences AP production and deposition
in a way analogous to the PS-I mutation [16, 17, 221.
T o investigate this possibility, we have used endspecific monoclonal antibodies that distinguish between
AP peptide species terminating at C4" and C42143j
and
have assessed the presence and amount of each peptide,
within the brains of patients from the Volga German
families, by using immunohistochemistry and image
analysis. We have compared the overall amount of each
peptide present in the same region of brain (superior
frontal cortex) as that seen in cases of sporadic AD and
cases in which AD is associated with PS-1 mutations
[221.
From the 'Department of Pathological Sciences, Division of Molecular Pathology, University of Manchester, Manchester, UK; i n e partment. of Neuropathology and Neuroscience, Faculty of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan: and
tDeparcrnent of Pathohby, Division of Neuropathology, and $Getiatric Research Education and Clinical Center and "Department of
Veterans Affairs, VA Medical Center, University of Washington,
Seattle, WA.
Received Apr 4, 1996, and in revised form May 21 and Jun 17.
Accepred for publication Jun 19, 1996.
52
Address correspondence to Dr Mann, Department of pathological
Sciences, University of Manchester, Stopford Building, Oxford
Road, ManChester 13 9PT, UK.
Copyright 0 1397 by the American Neurological Association
Table 1. Clinical and Pathological Details of 6 Cases of AD in Volga German Families
Case/
Code
Family/
Pedigreea
Neurologicall
Age at Age at
Onset Death Duration PS-2b
Psychological
Gender (yr)
(yr)
(yr)
Mutation Features
1. 12540
WIII-1
M
54
72
18
N'*~I
2. 18724 HBiIV-32
M
65
75
10
N14'I
3. 20692
R/IV-9
M
56
74
18
NL411
4. 9930
H/III-2
F
58
80
22
N'*lI
5. 15647 BE/III-7
M
62
69
7
N1*'I
6. 18385 HDiIV-64
F
49
59
10
N1*'I
'Data from Bird and colleagues [23, 241.
bData from Levy-Lahad and co-workers [13].
'Half-brain weight.
AD = Alzheimer's disease; PS-2 = presenilin-2; ApoE
=
Seizures
Blocks of frontal cortex (superior frontal gyri) (Brodmann
areas 8/9) and cerebellum were obtained from the formalinfixed brains of 6 members of 6 separate families within the
Volga German pedigrees (Table 1). These tissue blocks were
taken from topographical sites as close as possible to those
used in previous studies of ours on AD deposition in cases
of AD due to APP [19, 211 and PS-1 [22] gene mutations
and in cases of sporadic A D [19, 21, 221. Overall clinical
and pathological descriptions of these families have been presented elsewhere [23, 241, although brief details on these 6
particular family members are given in Table 1. Genetic analysis [13] has shown that affected members of the H, R, W,
HB, BE, and HD families all bear the characteristic NI4lI
PS-2 gene mutation.
All tissues were routinely processed (in Manchester) into
paraffin wax. Consecutive sections were cut at a thickness of
6 p m and stained with methenamine silver and immunostained using the end-specific monoclonal antibodies BA27
and BC05 to selectively demonstrate AD4,,- and AP42143)-immunoreactive plaques and blood vessels (see Reference 19 for
details of antibodies and staining method). BC05- and
BA27-immunostained sections were subjected to computerized morphometty (by TI) using an Olympus Image Analysis
System (SP1000, Model 1500 C2) as described previously
[19]. The numerical density and area proportion (amyloid
load) of BC05- and BA27-positive deposits (plaques) was
measured and the ratio of BA27 to BC05 deposits calculated
in terms of both relative density and relative area occupied.
Such data were compared with previously unpublished data
of ours from 16 cases of sporadic A D and with published
data from 8 other cases with AD due to PS-1 gene mutations
[22]. The sporadic AD cases were all without known previous family history of the disease and all had onset of illness
before 75 years of age (range, 52-75 years; mean, 63.6 2
8.9 years), similar to the Volga German cases (mean, 57.3
? 5.7 years; see Table 1). These sporadic AD cases were
Histopathology
Typical AD; severe CAA
Typical AD;
MS at age 55
mild CAA;
MS
Rigid, seizures, my- Typical AD; seoclonus
vere CAA
Delusions, language Severe AD; mild
disturbance
CAA
Explosive anger
Typical AD;
mild CAA
Early dysnomia
Typical AD;
mild CAA
apolipoprotein E; MS
Materials and Methods
Brain
=
Weight ApoE
(gm)
Genotype
355'
E3lE4
1,186
E3/E3
474'
E3lE3
955
E3/E3
1,142
E3lE3
1,200
E2lE3
multiple sclerosis; CAA = cerebral arnyloid angiopathy.
also selected according to apolipoprotein E (ApoE) genotype
(3, E2/E3; 11, E3/E3; 2 E31E4) so as to match, as proportionately close as possible, both the PS-2 cases (1, E2/E3; 4
E3/E3; 1 E31E4; see Table 1) and the previous PS-1 cases
(2, E2/E3; 5 E31E3; 1 E3/E4; see Reference 22), to avoid
the possibility that unequal variations in ApoE genotype distribution across the 3 groups might influence the comparisons of AP deposition.
Results
Histological Changes
Detailed histopathological descriptions of patients from
these families have been given elsewhere [23, 241. I n
b o t h the methenamine silver-stained sections and in
the BC05- a n d BA27-immunostained sections of frontal cortex, t h e distribution and a m o u n t of amyloid deposited as plaques in t h e 6 PS-2 cases appeared broadly
similar to that seen in the cases of sporadic AD. M a n y
diffuse a n d cored plaques were present throughout all
cortical layers, b u t these tended to b e more numerous
i n layer I1 and upper layer I11 (Fig IA). BC05 antibody
labeled a similar number of amyloid deposits as the
methenamine silver stain (Fig lB), irrespective of morphological type; BA27 antibody labeled only a subset
of plaques, this being associated mostly with cored
rather than diffuse plaques (Fig 1C). When present,
congophilic angiopathy (CAA) was usually mild o r
moderate b u t was severe in Patients 1 a n d 3. CAA was
strongly immunolabeled by BA27 antibody, usually
showing a n even distribution throughout the vessel
wall. BC05 antibody usually, b u t n o t always, stained
the same vessels as BA27, b u t here the immunoreaction
was weaker and often patchy in distribution through
the vessel wall (Table 2) (not shown).
Mann et al: Amyloid and Alzheimer's Disease
53
B
A
C
Fig 1. Consecutive sections offiontal cortex of Patient 4 stained with methenamine silver (A) and immunostained with BC05 (B)
and BA27 (C) antibody. There are numerous d@se and cored plaques throughout all cortical layers, although those in deeper byers tend to be larger and more strongly immunostained with both BC05 and BA27 antibodies. (All X 85.)
CAA was present in all 6 cases but was severe in only
1 (Patient 3); staining of CAA with BC05 and BA27
Diffuse deposits of amyloid were present in the molecular layer of the cerebellum of all 6 cases, although
these were only few or moderate in number. In some
cases (especially in Patient 4 ) cored deposits were seen
in the Purkinje cell layer (see Table 2). The diffuse
deposits were exclusively BC05 immunoreactive (Fig
2A and B), while the cored plaques were strongly BA27
immunoreactive (Fig 2D) and BC05 reactive (Fig 2C).
antibody was similar in pattern to that seen in the frontal cortex (see Table 2).
Morphometric Results
In the 6 PS-2 cases, with proven chromosome 1 linkage
and possession of NI4'I mutation, both the numerical
Table 2. Rating of Extent of Amyloid Deposition as Plaques or as Amyloid Angiopathy in Frontal Cortex and Cerebellum in 6
Cases of A D among Volga German Families
Frontal Cortex
Plaques
Patient I Code
1.
2.
3.
4.
12540
18724
20692
9930
5. 15647
6. 13385
Cerebellum
Vessels
Plaques
BC05
BA27
BC05
BA27
BC05
+++
+++
+++
++++
+++
+++
++
+
++
+++
0
+++"
+++"
++++"
++
0
0
+"
+ +"
01 +
++
++
+++
++++A
Vessels
BA27
BC05
BA27
01 +'
+c
01 +
01+
0
01 + h
0
0
0
01+
+++'
+S b
+"
+
+++'
0
01 +
01
01+'
+ +"
+++
+
+
++++
++
++
+c
+h
+'
'Intracorrical vessels also affected.
bDiffuse plaques in molecular layer.
'Cored plaques in granule and Purkinje cell layer.
++
+++
++++
= moderate;
= many;
= very many.
Plaques: 0 = absent; O / + = rare plaques staining; + = few;
Vessels: 0 = absent; O i = rare vessel staining;
= few vessels weakly or patchily stained; +
= few vessels strongly or evenly stained;
= many vessels weakly or patchily stained; + + + + = many vessels strongly or evenly stained.
+++
+
54 Annals of Neurology Vol 41
+
No 1 January 1997
+
A
B
C
D
Fig 2. Consecutive sections of cerebellar cortex $Patient 4 irnmunostained with BC05 (A and c)and BA27 (B and 0)antibody The difise plaques in the molecular hyer are BC05 positive (A) but BA27 negative (B), whereas the cored phques in the
positive. (A and B, X 85; c and 0,
X 170.)
Purkznje cell layer are both BC05 (C) and BA27 (especially) (0)
density and area proportion of BC05 (AP42(43)- and
BA27 (AP&immunoreactive deposits (plaques) in the
frontal cortex were similar to equivalent measures in
the frontal cortex of the 16 patients with sporadic AD
(Table 3). Such measures in the Volga German patients
were, however, substantially less than equivalent measures in 8 cases of AD due to PS-1 gene mutation (see
Table 3 ) . In all 3 groups, the ratio between BA27 and
BC05 immunoreactivities was similar, in terms of both
numerical density of plaques and the area proportion
of tissue occupied (amyloid load) (see Table 3). While
the extent of AP deposition, as AP42(4j),
tended to correlate ( y S = 0.8; p < 0.1) with duration of illness in the
Volga German cases both for plaque density and amyloid load, no tendency toward a similar relationship
was seen either for AP40measures or for values of the
ratio between AP4fland AP42(41)deposition.
Discussion
As we, and others, have shown in sporadic AD [19,
25, 261, familial AD due to mutations in both the APP
[19-21] and the PS-1 [22] genes, Down’s syndrome
[27], and in the nondemented elderly [28], the predominant peptide species deposited within plaques in
AD due to the PS-2 gene mutation within the Volga
German families is again AP42(43). Likewise, as in the
aforementioned etiological variants of AD, there are
many plaques in the PS-2 cases that are AP42(43)positive
but AP40 negative, implying that here also AP42(43)
is
the peptide that is initially deposited as plaques, with
AP40 appearing only later, in a subset of these plaques,
during the course of their evolution or maturation.
Furthermore, the proportion of AP deposited as AP4fl
does not differ in PS-2 cases of AD from that seen in
sporadic AD, AD due to PS-1 gene mutations, or
Down’s syndrome [21, 22, 271.
However, it is noteworthy that the overall amount
of AP42(43)and AP4,, deposited in AD due to PS-2 gene
mutation does nor differ from that deposited in sporadic AD, either in terms of the number of deposits
present or the percentage of area of tissue occupied,
and is significantly less (at least in terms of percentage
of area of tissue occupied, with a tendency to be lower
in terms of plaque number) than that in AD due to
Mann et al: Amyloid and Alzheimer’s Disease
55
Table 3. Numerical Density and Area Proportion of BC05- and BA27-immunoreactive Deposits in A D Within the VoLga
German Families, in Sporadic A D and in A D Due to PS-1 Gene Mutations, (Ratios Between BA27 and BC05 Values
Are Given)
Number of Amyloid Deposits (mm-')
Patient/Code
BC05
BA27
1. 12540
2. 18724
3. 20692
4. 9930
5. 15647
6. 18385
Mean (-+SD) PS-2
AD (patients 1-6)
Mean ( i S D ) sporadic AD
Mean (?SD) PS-1
AD'
155.0
55.4
188.0
223.0
106.0
34.7
3.6
Ratio
BA27/BC05
Percentage of Area of Amyloid
BC05
BA27
Ratio
BA27/BC05
11.1
2.7
9.3
10.0
6.1
8.3
7.9" i 3.1
1.6
0.2
0.9
3.5
1.6
3.6
1.9b 2 1.4
0.14
0.07
0.10
0.35
0.26
0.43
0.23 t- 0.15
133.5* i 66.2
106.0
48.3
51.8
42.4J 2 36.9
0.22
0.07
0.05
0.48
0.46
0.71
0.33 t 0.26
146.3 t- 70.4
45.7 t 47.1
0.31 ? 0.20
5.0 -C 2.4
2.1 2 2.3
0.35 ? 0.33
223.9' 2 124.9
73.8' i 38.7
0.38 t- 0.21
14.0" 2 5.4
4.0' ? 2.5
0.28 i 0.18
9.9
73.3
'Difference from PS-1 AD, 0.1 > p > 0.05.
hSignificantlydifferent from PS-1 AD, p < 0.05.
'"Significantly different from sporadic AD; p < 0.01, p < 0.001, respectively.
'Data previously published by Mann and colleagues [22].
AD = Alzheimer's disease; PS-1
=
presenilin-1; PS-2 = presenilin-1.
PS-1 gene mutations. This lack of difference in the
extent of AP deposition between the Volga German
cases and the cases of sporadic AD, and their less extensive deposition when compared with cases of AD due
to PS-1 gene mutations, is unlikely to simply reflect an
unusually short duration of illness in the Volga German
group that might curtail the pathological process at a
relatively early stage. The mean duration of illness in
the 6 PS-2 cases (14.6 -t 5.9 years) was, in fact, significantly longer than the average duration of illness in
either the sporadic (9.0 2 2.6 years) or the PS-1 (9.4
t 6.2 years) AD groups with which they are compared, indicating the (unusually) slowly progressive nature of the disease in this form of AD.
Thus, present data suggest either that the PS-1 and
PS-2 gene mutations influence the development of AD
in different ways or that the PS-2 gene mutation, while
conferring a similar mechanistic susceptibility to disease acquisition, has a much less powerful effect than
the PS-1 gene mutation. Given the general homologies
between PS-1 and PS-2 gene structures-both
genes
share a 67% homology overall, which rises to 84%
within the putative transmembrane domains [ 13]-the
latter possibility seems more likely. Hence, both PS-1
and PS-2 gene mutations may operate along similar
pathogenetic routes, with the more powerful PS-I mutation conferring a more aggressive development of pathology than the PS-2 gene mutation whose effects
seem to build only very slowly over a prolonged period
of time. Such a suggestion would also be in keeping
with the differences in onset age; patients with AD due
56 Annals of' Neurology Vol 41 No 1 January 1997
a PS-1 gene mutation usually have onset age between
30 and 50 years of age, whereas the Volga German
patients with the PS-2 mutation have a wider range of
onset age, often (as here) commencing after 50 years
of age ([23, 241; Bird TD, Levy-Lahad E, Poorkaj P,
et al, unpublished data).
Because the PS-1 gene mutation is associated with
an increased production of AP1.42, at least in cultured
fibroblasts from affected carriers [16, 171, and an elevated level of the same peptide species within the
plasma of such individuals [16, 171, it is possible that
this particular mutation confers a cellular defect that
favors catabolism of APP along pathways leading to AP
formation. However, this may not necessarily be so for
the PS-2 mutation, since it is currently not known
whether production of AP1.I2 is indeed increased in
bearers of this mutation and, moreover, tissue deposits
of AP42 are no different from those in sporadic AD.
The presenilin (PS) proteins seem to be preferentially
located in nerve cells and within internal membranes,
probably those of the Golgi and endoplasmic reticulum
[23]; they may therefore play a role in the trafficking
of newly formed proteins through these organelles.
Hence, one effect of the PS gene mutations may be to
deter protein transport or to direct it to inappropriate
sites for degradation. In the case of APP, this may become preferentially directed toward secretory vesicles
where degradation to AP via p-secretase action may
then occur [30].
In summary, therefore, this present study has shown
that in AD due to the PS-2 gene mutation, AP42(43)
is
the primary and predominant AP peptide species deposited in rhe brain. Such data agree with findings in
other inherited forms of AD [19-221, sporadic AD
[19, 25, 261, Down’s sydrome [27],and in the nondemented elderly [28] and further imply that the formation of this particular AP peptide may represent the
common starting point in the pathogenetic cascade of
AD on which all etiological forms become focused.
The finding of elevated amounts of soluble AP42 in the
brains of young persons with Down’s syndrome, even
before APu-containing plaques become present in the
tissue [3I], substantiates this conclusion.
The study was supported in part by grants from the NIA (AGO5136
to the Alzheimer’s disease Research Centre and AG06781-06 to the
Alzheimer’s Disease Patient Registry, University of Washington,
and Veterans Affairs Research Funds).
We thank Mrs M. Barringer for the preparation of the manuscript
and Mr T. like and Mr M. Kato (of Olympus Co, Ltd) for technical
assistance. Dr G. Schellenberg performed the APO E genotyping.
References
1. Mullan M, Tsuji S, Miki T, et al. Clinical comparison of Alzheimer’s disease in pedigrees with the codon 717 Val-Ile mutation in the amyloid precursor protein gene. Neurobiol Aging
1993;14:407-419
2. Lannfelt L, Bogdanovic N, Appelgren H, et al. Amyloid precursor protein mutation causes Alzheimer’s disease in a Swedish
family. Neurosci Lett 1994;168:254-256.
3. Campion D, Flaman J-M, Brice A, et al. Mutations of the
presenilin 1 gene in families with early-onset Alzheimer’s disease. Hum Mol Genet 1995;4:2373-2377
4. Clark RF, Hutton M, Fuldner R, et al. The structure of the
presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nature Genet 1995;11:219222
5. Cruts M, Backhovens H, Wang S-Y, et al. Molecular genetic
analysis of familial early-onset Alzheimer’s disease linked to
chromosome 14q 24.3. Hum Mol Genet 1995;4:2363-2371
6. Perez-Tur J, Frodlich S, Prihar G, et al. A mutation in Alzheimer’s disease destroying a splice acceptor site in the presenilin1 gene. Neuroreport 1996;7:204-207
7. Sherrington R, Rogaev EI, Liang Y, et al. Cloning of a novel
gene bearing missense mutations in early onset familial Alzheimer’s disease. Nature 1995;375:754-760
8. Sorbi S, Nacmias B, Forleo P, et al. Missense mutation of S182
gene in Italian families with early-onset Alzheimer’s disease.
Lancet 1995;346:439-440
9. Tanahashi H, Mitsunaga Y, Takahashi K, et al. Missense mutation of S182 gene in Japanese familial Alzheimer’s disease. Lancet 1995;346:440 (Abstract)
10 Van Broeckhoven C. Presenilins and Alzheimer’s disease. Nature Genet 1995;1 1:230-232
11. Wasco W, Pettingell WP, Jondro PD, et al. Familial Alzheimer’s chromosome 14 mutations. Nature Med 1995;1:848
22. Levy-Lahad E, Wijsman EM, Nemens E, et al. A familial Alzheimer’s disease locus on chromosome 1. Science 1995;269:
970-973
13. Levy-Lahad E, Wasco W, Poorkaj P, et al. Candidate gene for
the chromosome 1 familial Alzheimer’s disease locus. Science
1995;269:973-977
14. Rogaev EI, Sherrington R, Rogaeva EA, et al. Familial Alzheimer’s disease in kindreds with missense mutations i n a gene
on chromosome 1 related to the Alzheimer’s disease type 3
gene. Nature 1995;376:775-778
15. Suzuki N, Cheung TT, Cai X-D, et al. An increased pcrccncage
of long amyloid P protein secreted by familial amyloid p protein precursor (pAPP717) mutants. Science 1994;264:13361340
16. Scheuner D , Song X-H, Younkin SG, et al. Fibrohlasts from
carriers of familial AD linked to chromsome 14 show increased
AP production. SOCNeurosci Abstr 1995;21:1500 (Abstract)
17. Younkin SG, Song X-H, Scheuner D , et al. The amyloid P
protein in familial Alzheimer‘s disease (FAD): a study based
on plasma and fibroblasts from known carriers. International
Society for Neurochemistry, 1995, Kyoto, Japan (Abstract)
18. Jarrett JT, Berger EP, Lansbury PT. The carboxy terminus of
the P-amyloid protein is critical for the seeding of amyloid
formation. Implications for the pathogenesis of Alzheimer‘s disease. Biochemistry 1993;32:4693-4697
19. Iwatsubo T, Odaka A, Suzuki N, et al. Visualization of
A\842(43) and AD40 in senile plaques with end-specific ADmonoclonals: evidence that an initially deposited AD species is
AP42(43). Neuron 1994;13:45-53
20. Tamaoka A, Odaka A, Ishibashi Y, et al. APP717 mis-sense
mutation affects the ratio of amyloid p protein species ( A p l 42/43 and Apl-40) in familial Alzheimer’s disease brain. J Biol
Chem 1994;269:32721-32724
21. Mann DMA, Iwatsubo T, Ihara Y, et al. Predominant deposition of amyloid-pdL(ii)
in plaques in cases of Alzheimer’s disease
and hereditary cerebral haemorrhage associated with mutations
in the amyloid precursor protein gene. Am J Pathol 1996;148:
1257- 1266
22. Mann DMA, Iwatsubo T, Cairns NJ, et al. Amyloid (AD) deposition in chromosome 14-linked Alzheimer’s disease: predominance of AP42(43). Ann Neurol 1996;40:149-151
23. Bird T D , Lampe T H , Nemens EJ, et al. Familial Alzheimer’s
disease in American descendants of the Volga Germans: probable genetic founder effect. Ann Neurol 1988;23:25-31
24. Bird TD, Sumi SM, Nemens EJ, et al. Phenotypic heterogeneicy in familial Alzheimer’s disease: a study of 24 kindreds. Ann
Neurol 1989;25:12-25
25. Mak K, Yang F, Vinters HV, et al. Polyclonals to p-arnyloid
(1-42) identify most plaque and vascular deposits in Alzheimer
cortex, but not striatum. Brain Res 1994;667:138-142
26. Murphy GM, Forno LS, Higgins L, et al. Development of a
monoclonal antibody specific for the COOH-terminal of pamyloid 1-42 and its immunohistochemical reactivity in Alzheimer’s disease and related disorders. Am J Pathol 1994;144:
1082-1088
27 Iwatsubo T, Mann DMA, Odaka A, et al. Amyloid p protein
(Ap) deposition: Ap42(43) precedes AP40 in Down syndrome.
Ann Neurol 1995;37:294-299
28 Fukumoto H, Asami-Odaka A, Suzuki N , et al. Amyloid p
protein (Ap) deposition in normal aging has the same characteristics as that in Alzheimer’s disease: predominance of
Ap42(43) and association of Ap40 with cored plaques. Am J
Pathol 1996;148:259-265
29. Kovacs D, Fausett HJ, Page KJ, et al. Alzheimer-associated
presenilins 1 and 2: neuronal expression in brain and localization to intra-cellular membranes in mammalian cells. Nature
Med 1996;2:224-229
30. Haass C, Lemere CA, Cape11 A, et al. The Swedish mutation
causes early-onset Alzheimer’s disease by P-secrerase cleavage
within the secretory pathway. Nature Med 1995;1:1291-1236
31. Teller JK, Russo C, De Busk LM, et al. Presence of soluble
amyloid P peptide precedes amyloid plaque formation in
Down’s syndrome. Nature Med 1996;2:93-95
Mann et al: Amyloid and Alzheimer’s Disease
57
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