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Regular Article |
From the Clinical Neuroscience Research Group,*
Department of Medicine, University of Manchester, Manchester, United
Kingdom; the School of Biological Sciences,
University of Manchester, Manchester, United Kingdom; and the
Department of Neuropathology and
Neuroscience,
University of Tokyo, Tokyo,
Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-secretase. We
report here a striking correlation between amyloid angiopathy and the
location of mutation in PS-1 linked Alzheimer’s disease. The amount of
amyloid ß protein, Aß42(43), but not
Aß40, deposited in the frontal cortex of the
brain is increased in 54 cases of early-onset familial Alzheimer’s
disease, encompassing 25 mutations in the presenilin-1 (PS-1)
gene, compared to sporadic Alzheimer’s disease. The amount of
Aß40 in PS-1 Alzheimer’s disease varied according to the
copy number of 
4 alleles of the Apolipoprotein E gene. Although the
amounts of Aß40 and Aß42(43) deposited did
not correlate with the genetic location of the mutation in a strict
linear sense, the histological profile did so vary. Cases with
mutations between codon 1 and 200 showed, in frontal
cortex, many diffuse plaques, few cored
plaques, and mild or moderate amyloid angiopathy. Cases with
mutations occurring after codon 200 also showed many diffuse
plaques, but the number and size of cored plaques were
increased (even when 4 allele was not present) and these were often
clustered around blood vessels severely affected by amyloid angiopathy.
Similarly, diverging histological profiles, mainly
according to the degree of amyloid angiopathy, were seen in the
cerebellum. Mutations in the PS-1 gene may therefore alter the topology
of the PS-1 protein so as to favor Aß formation and
deposition, generally, but also to facilitate amyloid
angiopathy particularly in cases in which the mutation lies beyond
codon 200. Finally we report that the amount of Aß42(43)
deposited in the brain correlated with the amount of this produced in
culture by cells bearing the equivalent mutations.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the central nervous system, PS-1 protein is principally located in
the perikarya and dendrites of neurones, particularly pyramidal cells
of the cerebral cortex and hippocampus and magnocellular basal
forebrain neurones, within the Golgi apparatus and smooth endoplasmic
reticulum.1-3
No differences in the distribution or amount
of immunocytochemically detectable PS-1 protein4-6
or its
message7
have been observed between AD (including cases of
PS-1 AD) and control patients. Nonetheless, cell lines and transgenic
mice bearing PS-1 [and presenilin-2 (PS-2)] mutations produce more
amyloid ß protein (Aß), particularly
Aß42(43) than those carrying wild-type
PS-1.8-13
Moreover, fibroblasts from human carriers of
PS-1 mutations produce more Aß42(43) in
culture14
and plasma levels of this are likewise elevated
in affected individuals.14,15
At autopsy, cerebral
cortical deposition of Aß, particularly
Aß42(43) is often high.16-20
Mutations in the PS-1 gene may therefore confer a metabolic defect that
modifies -secretase catabolism of APP along pathways that favor the
production of Aß, especially Aß42(43)
Recent evidence has indicated that both PS-1 and PS-2 are novel
membrane-associated aspartyl proteases,21
consistent with
the long-suspected idea that they regulate the catabolic activity of
-secretase and might even be -secretase itself. PS-1 knockout
mice show normal 
- and ß-secretase activity, although the activity
of -secretase and the production of Aß1-40
and Aß1-42 is decreased.20
Site
directed mutagenesis of the aspartate residues of PS-1 reduces
-secretase catalyzed processing of APP within its transmembrane
domain.21
Immunodepletion of PS-1 from solubilized
-secretase causes a reduction in -secretase activity and
solubilized -secretase activity co-migrates with PS-1 during gel
exclusion chromatography.22
Crossing linking experiments
using inhibitors of -secretase, directed to the active site of an
aspartyl protease, label PS-1 (and PS-2)23,24
and strongly
suggest that PS-1 (and PS-2) contain the active site of
-secretase.23
However, PS-1 (and PS-2) are probably
contained in a large functional complex with other
proteins.21,22,24
Studying factors that might influence variability in disease onset,
progression, or pathology in AD can be confounded by the heterogeneous
basis of the disease, eg, genetic (ApoE 4 allele) or environmental
(head injury) causes. To avoid such difficulties and therefore increase
the power of this type of study, we have investigated a large group of
patients with AD because of the same definable cause, ie, those with
PS-1 mutations. To determine the biological effects of mutations in the
PS-1 gene in the human situation, we have characterized the extent and
the morphological features of Aß deposition in 54 cases of PS-1 AD
from 25 separate mutations covering the length of PS-1. Deposition of
Aß40 and Aß42(43) as
plaques and amyloid angiopathy, was assessed in frontal cortex and
cerebellum and quantified by image analysis, and related to mutation
position in PS-1.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. These tissues were kindly
donated by colleagues throughout the world for this particular project
and no tissue blocks from other regions of cerebral cortex, or
noncortical areas, were available to us to study. Tissue blocks from a
similar area of frontal cortex were also available from 25 cases of
sporadic AD (SAD) with onset of disease before 70 years of age,
matching (proportionately) the cases of PS-1 AD for Apolipoprotein E
genotype (ApoE). All tissue blocks were similarly and routinely
processed into paraffin wax and consecutive sections, cut at a
thickness of 6 µm, were mounted onto 3-aminopropyltriethoxysilane
(APES)-coated slides.
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In histological sections the extent of Aß40 and Aß42(43) deposition within plaques (cerebellum only), or as amyloid angiopathy (frontal cortex and cerebellum), was rated semiquantitatively by an experienced neuropathologist (DMAM) according to the following protocol. Rating of plaques was: 1 = few; 2 = moderate; 3 = many; 4 = very many. The presence of subpial or white matter deposits was noted. Rating of amyloid angiopathy was: 1 = few leptomeningeal vessels weakly or patchily stained; 2 = few leptomeningeal vessels, strongly or evenly stained, with mild intracortical vascular involvement; 3 = many leptomeningeal and intracortical vessels patchily or strongly stained; 4 = many leptomeningeal and intracortical vessels strongly or evenly stained, with dyshoric angiopathy.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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There was much variation in the amount of
Aß42(43) deposited as plaques within the
frontal cortex between cases of different PS-1 mutation, and sometimes
within cases of the same mutation (Figure 1A)
. On average, some mutations were
associated with a very heavy Aß42(43)
deposition, some 2 to 3 times the amount of that in others in which
deposition was within the usual range (for SAD)27
with
<10% of tissue area occupied. There was no obvious clustering of
mutations associated with high, intermediate, or low Aß deposition at
any site(s) (in a strict linear sense) within the PS-1 gene. More
importantly, there was no apparent clustering of high- or
low-Aß42(43)-depositing mutations around the
active site aspartyl residues at codon 257 and 385, or around codon 298
where PS-1 is cleaved.28
Nonetheless, present findings
clearly imply that some mutations are much more aggressive than others,
at least in terms of the extent of tissue deposition of
Aß42(43) they elicit.
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.
There was no correlation between the amounts of
Aß40 and Aß42(43)
within plaques across the 54 cases. Comparisons with Sporadic AD
The area proportion of tissue occupied by Aß42(43)-containing plaques was overall significantly (P < 0.001) higher in PS-1 AD compared to SAD (13.6 ± 5.9% versus 7.6 ± 2.3%, respectively). However, the area occupied by Aß40 in PS-1 AD did not differ overall from that in SAD (2.5 ± 3.7 versus 2.2 ± 2.2, respectively). Such data extend previous studies based on small series of patients or on individual cases.16-20 They are also consistent with experimental studies using cell lines and transgenic mice,8-13 or fibroblasts from human carriers14 showing that the PS-1 mutations result in an increased production of Aß42(43) but not Aß40, compared to wild-type PS-1.
Relationship between Aß Deposition and ApoE Genotype
We stratified the PS-1 and SAD cases according to ApoE genotype,
grouping into 4 and non-4 allele bearers. The area proportion of
tissue occupied by Aß42(43) was significantly
greater in PS-1 AD, compared to SAD, for both non-4 (13.2 ±
6.5 versus 8.1 ± 2.9, respectively; P
< 0.01) and 4 (14.9 ± 4.8 versus 7.2 ± 1.6,
respectively; P < 0.001) allele bearers. Area measures
for Aß40 did not however differ from those of
SAD, either for non-4 (1.8 ± 2.9% versus 1.1
± 0.9%, respectively) or 4 (4.1 ± 5.3% versus
3.2 ± 2.7%, respectively) allele bearers. Nevertheless, as
we27
and others29
have reported previously
for SAD, the area proportion of tissue occupied by
Aß40, but not Aß42(43)
was greater (P < 0.05) in cases of PS-1 AD in
the presence of 4 allele (with 4 4.1 ± 5.3%
versus 1.8 ± 2.9% without 4). Such data imply that
the presence of E4 protein isoform in the brain in PS-1 AD may, as in
SAD, lower the threshold to fibrillization of
Aß40, thereby promoting its deposition on
pre-existing Aß42(43)-containing plaques.
Relationship between Aß Deposition and Aß Production
We correlated the mean amount of
Aß42(43) deposited in the frontal cortex in 19
of the PS-1 mutations with the amount of Aß1-42
secreted in culture by Green monkey kidney cells (COS-1 cells) bearing
the same mutations. This latter data30
was obtained with
permission from Professor T. Iwatsubo, University of Tokyo. We
found a significant (r = 0.789,
P < 0.001) correlation between the amount of tissue
deposition in human brain and secretion of Aß in culture for each
PS-1 mutation (Figure 2)
. This indicates
that variations in the amount of Aß deposited in the tissue reflect
differences in the level of production of Aß. Tissue deposition of
Aß can therefore be viewed as an index of tissue secretion. Moreover,
these results reinforce the utility of cell lines for investigating the
effects of PS-1 mutations in vivo.
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As has been observed previously,16-19
amyloid
angiopathy was particularly prominent within the frontal cortex of many
of the present cases, this involving both intraparenchymal, as well as
leptomeningeal, vessels with a dyshoric change being commonplace
(Figure 3, c and d)
. Indeed, a
particularly heavy Aß40 deposition, in the form
of large plaques clustered around affected vessels, was seen in cases
with severe amyloid angiopathy, especially when dyshoric angiopathy was
present (Figure 3d)
. Variations in plaque Aß40
(but not Aß42(43) deposition) correlated
(Rs = 0.672; P < 0.001) with the rating for
amyloid angiopathy. These observations suggest a possible hematogenous
source for at least some of the Aß40, with
plasma Aß40 leaking across damaged blood
vessels and seeding on local pre-existing
Aß42(43)-containing deposits. Although some
cases with severe amyloid angiopathy were bearers of ApoE 4 allele,
there was no correlation between possession of this and the extent of
amyloid angiopathy across the 54 cases (data not shown).
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with most of those cases showing
heavier pathology (ie, grade 2 and above) (27 of 34) occurring after
codon 200. This differed significantly (chi-square = 15.4;
P < 0.001) from that proportion (5 of 20) of cases
with heavy pathology occurring before codon 200.
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We then examined the overall pattern of plaque and vessel Aß deposition in the 54 cases of PS-1 linked AD. It was strikingly clear that there were two distinct topographical profiles, defined as type 1 and type 2.
Type 1
In this pattern of pathology BC05
(Aß42(43)) immunostaining revealed many diffuse
and cored plaques, fairly evenly distributed along the whole of the
gyral length (Figure 3a)
. Usually, more plaques were present in
cortical layers II and upper III, where diffuse deposits predominated,
than in layers V and VI where cored plaques were more frequent. Cored
plaques were also more frequent at the depths of the cortical sulci
(Figure 3a)
. Relatively few subpial deposits were seen and only
occasional white matter plaques were present. In BA27
(Aß40) immunostaining either a few, or a
moderate number of, small cored or compacted deposits were fairly
evenly spread along cortical laminae (usually in layers II and III) but
often concentrated at the depths of the cortical sulci (Figure 3b)
. A
few subpial deposits were stained and occasional white matter plaques
were present. In both BC05 and BA27 immunostaining, amyloid angiopathy
was mild or moderate (or sometimes absent) and confined mostly to
leptomeningeal arteries, with only occasional intraparenchymal arteries
being involved.
Type 2
In this pattern of pathology, BC05 immunostaining revealed a
similar number and distribution of diffuse and compacted or cored
plaques as in type 1 pathology, except these tended to be very large
and concentrated around amyloidotic arteries, especially at the depths
of sulci (Figure 3c)
. In BA27 immunostaining many of the diffuse
plaques were weakly immunoreactive, although often there were many,
very large, cored plaques clustered, as large conglomerates, around the
amyloidotic arteries (Figure 3d)
. Amyloid angiopathy was nearly always
severe, involving both leptomeningeal and intraparenchymal arteries,
and dyshoric change was frequent (Figure 3, c and d)
.
The distribution of type 1 and type 2 histologies within frontal cortex
of individual cases, with respect to mutation site, is given in Figure 5
. Sixteen of 21 cases with type 1
histology occurred before codon 200 whereas 29 of 33 cases with type 2
histology occurred beyond codon 200. These distributions of
pathological subtype either side of codon 200 were, in both instances,
highly significantly different (chi-square = 22.6,
P < 0.001).
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and three from a Japanese pedigree. All three members of the Japanese
pedigree had type 2 histology, whereas one of the American cases had
type 1 histology whereas the other, a bearer of ApoE 4 allele, had
type 2 histology. Similarly, of the six bearers of A246E mutation,
three had type 1 histology and were all bearers of ApoE 3/3
genotype whereas the other three were bearers of ApoE 4 allele and
had type 2 histology. In contrast, of the five bearers of the G209V
mutation, one had type 1 histology and four had type 2 histology, yet
all bore the ApoE 3/3 genotype. Comparisons between Type 1 and Type 2 Histologies
Comparing the mean age at onset (±SD) between type 1
(n = 21; 41.5 ± 7.7 years) and type 2
(n = 32; 46.7 ± 6.6 years) histologies, we
found that type 1 cases had a disease onset (P =
0.012) on average 5 years before type 2 cases. A similar trend was also
observed for disease duration with type 1 cases
(n = 21; 7.9 ± 4.6) being 2.4 years
shorter (P = 0.081) than type 2 cases
(n = 32; 10.3 ± 5.6 years). Furthermore,
there was a near significant difference (P =
0.067) in the mean percentage area occupied by
Aß42(43) (type 1,
n = 21, 15.3 ± 6.5%; type 2,
n = 33, 12.4 ± 5.4%). The opposite trend was
observed with the mean percentage area occupied by
Aß40 with type 2 (n =
33, 2.9 ± 3.4%) having significantly more
(P = 0.009) than type 1
(n = 21, 1.8 ± 4.1%) cases. Moreover, 5
of 21 type 1 cases had Aß40 levels >2% (1 of
21 >3%), whereas 11 of 33 cases with type 2 histology had
Aß40 levels >2% (9 of 33 >3%). Thus
although only 1 of 21 cases with type 1 histology had high (ie, >3%)
levels of Aß40, 9 of 33 cases with type 2
histology had Aß40 levels above this
(chi-square = 4.3; P < 0.05). Thus there was an
overall tendency for Aß40 deposition to be
greater, and to occur more frequently in type 2 histology cases,
although this association was far from perfect. The differences in
Aß40 and Aß42(43)
deposition between type 1 and 2 histologies were independent of ApoE
gene effects as similar numbers of 4 allele bearers were present in
each group (type 1, 6 of 21; type 2, 8 of 31; chi-square = 0.05;
P > 0.05). Indeed, among those cases with type 2
histology, the average rating for amyloid angiopathy in bearers of 4
allele (2.5) was similar to that in nonbearers (2.54).
Changes in the Cerebellum
We next examined the patterns of histological change within the cerebellum of 48 of the 54 cases where this region was also available. Aß deposition, both as plaques and as amyloid angiopathy, was seen in all cases, although only trace amounts of amyloid angiopathy were seen in two cases. Again, two distinct histological patterns of Aß deposition were seen.
Type 1 Histology
In BC05-immunostained sections either a moderate number of, or
many, diffuse plaques were seen in the molecular layer, some of which
contained areas where the amyloid was more compacted (Figure 6a)
. Cored plaques, similar to those
typically seen in the cerebral cortex, were also occasionally seen in
the molecular layer. In most instances a few or a moderate number of
cored, or more often irregular-shaped, coarse amyloid deposits were
usually present in the Purkinje cell layer or granule cell layer
(Figure 6a)
. Amyloid angiopathy was mild, moderate, or severe,
sometimes affecting intracortical, as well as leptomeningeal, vessels
(Figure 6a)
and occasionally with dyshoric change.
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. The
cored plaques in the Purkinje and granule cell layers were nearly
always BA27 immunoreactive, usually strongly so (Figure 6b)
. Amyloid
angiopathy distribution was as seen in BC05 immunoreaction, although
usually more strongly staining (Figure 6b)
. Type 2 Histology
In BC05-immunostained sections there were usually fewer diffuse
plaques (than in type 1 histology) (Figure 6c)
and often none at all.
Well-defined cored plaques were always present in all layers and in
many instances were much more numerous than in cases with type 1
histology, especially within the granule cell layer. Coarse, irregular
deposits were more common than the discrete cored plaques in some
instances and these were particularly numerous within Purkinje and
granule cell layers (Figure 6c)
.
In BA27-immunostained sections only rare patches of immunoreaction were
seen in compacted regions of the diffuse plaques (Figure 6d)
. However,
the cored and coarse deposits in the molecular, Purkinje (Figure 6d)
,
and granule cell layers were always strongly immunoreactive. Amyloid
angiopathy was generally more severe (Figure 6, c and d)
. In most
instances intracortical, as well as leptomeningeal, vessels were
affected, sometimes with dyshoric change.
The distribution of cerebellar type 1 and type 2 histologies within
individual cases with respect to mutation site is given in Figure 5
.
Fourteen of 24 cases with type 1 histology occurred before codon 200
whereas 22 of 24 cases with type 2 histology occurred beyond codon 200.
These distributions of histological subtype either side of codon 200
were again, in both instances, highly significantly different
(chi-square = 13.5; P < 0.001).
Correlations between type 1 and type 2 histologies in frontal cortex
and cerebellum (Figure 5)
in the 48 cases in which both regions were
available for study revealed a coincidence of histological type in 42
of the cases. There was only one case (case 12 with M146I mutation)
with type 1 histology in the frontal cortex that did not also have type
1 histology in the cerebellum. Conversely, there were five cases (two
with G209V mutation and three with E280A mutation) with type 2
histology in the frontal cortex that did not also have type 2 histology
in the cerebellum.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It is common, indeed usual, to find marked anatomical variations in the distribution and severity of the characteristic pathological changes of AD (ie, amyloid plaques, amyloid angiopathy, and neurofibrillary tangles) throughout the brain. However, because the histological distinctions seen in the frontal cortex also occur in the cerebellum of the same cases, we feel that this pattern of pathology would be similarly mirrored in other topographical brain regions. Unfortunately, no other brain regions were available to us for this present study, and clearly this is an issue that will require further study.
A severe involvement of the cerebellum in PS-1 AD by Aß deposition (plaque formation) has been noted on previous occasions in respect of particular mutations (eg, E280A,17 I143T,31 M139V,16,32,33 G209V16,33,34 ). Findings reported here are consistent with these previous descriptions, although this present study has extended the range of PS-1 mutations examined, allowing comparisons to be made between many more of the mutations associated with this form of AD. In sporadic AD, cored and coarse Aß deposits in the cerebellum, of the kind described here in PS-1 AD, are rare.35-38 However, the high presence of these is not specific to PS-1 AD and such deposits can be found in the brains of elderly patients with Down’s syndrome35-37,39-41 and AD because of APP717 mutation.42 The observation17 of an especially high PS-1 mRNA expression in PS-1 AD (E280A) compared to sporadic AD may have relevance to the unusually severe cerebellar pathology seen in this particular mutation, and perhaps others. However, it may just be that PS-1 mutations, like the APP717 mutations and the trisomy of Down’s syndrome, have such a devastating effect on the brain that the pathology progresses more severely into peripherally affected regions, like the cerebellum, when compared to sporadic AD.
Broadly speaking, the two histological phenotypes in cerebral cortex
and cerebellum are associated with mutations grouping toward opposite
ends of the PS-1 gene structure. The type 1 histological profile is
generally seen in cases with mutations extending up to codon 200, with
type 2 profiles following codon 200. However, some overlap does occur.
For example, in G209V, A246E, and E280A mutations, there are cases with
type 1 or type 2 histology. Although the eight cases with E280A
mutations were spread between several families, all cases with A246E or
G209V mutations were from the same kindreds. Furthermore, the M146I
mutation is associated with type 2 histology, when other mutations at
the same codon (M146L and M146V) produce type 1 histology. This implies
that there may perhaps be other (genetic) modifiers that act in concert
with PS-1 to determine the histological phenotype, although possession
of ApoE 4 allele does not seem to be instrumental in this respect.
There are other mutations in PS-1 gene also associated with AD
phenotype. In at least four pedigrees43-48
there is a
functional deletion of exon 9 (
E9) that occurs either because of
missense mutations that result in splice acceptor site
changes44-46
or as a result of a 4.5-kb
deletion47,48
within exon 9. Although these mutational
events lie beyond codon 200 in the PS-1 gene, they are not associated
with the type 2 histology, as above. These exon 9 deletion cases are
characterized histologically by very large, rounded plaques within the
frontal cortex, known as "cotton wool"
plaques.43,48,49
These are composed of both
Aß40 and Aß42(43) and
are relatively free from neuritic changes and glial cell components,
and usually devoid of a compact amyloid core.49
In the
cerebellum the plaques are almost entirely of a compact type, again
composed of Aß40 and
Aß42(43) with only a few diffuse
Aß42(43)-containing plaques.49
The
amount of Aß40, and the ratio between
Aß40 and Aß42(43) in
frontal cortex, is higher than that seen in other cases of AD because
of different PS-1 mutations, or in cases of sporadic AD, of similar
ApoE genotype.49
Amyloid angiopathy in frontal cortex and
cerebellum is highly variable.49
This kind of histological
picture was not seen in any of the PS-1 cases studied here, even in
those (eg, E280A, L286V) in which the mutation is located close to the
splice acceptor site at codons 289/290. Furthermore, these exon 9
deletion cases often present clinically with a spastic
paraparesis.43,48
To our knowledge, none of the PS-1 cases
studied here displayed such clinical features. Hence, the exon 9
deletion cases would seem to present a separate distinct histological
(and clinical) subtype, despite the mutational events that cause such
changes being located after codon 200.
How these tissue variations in Aß40 and
Aß42(43) deposition in the form of plaques, or
the presence and extent of amyloid angiopathy, producing two clearly
distinguishable histological profiles might relate to PS-1 protein
structure or mutant PS-1 protein topology is unclear. Possession of
ApoE 4 allele, which in the cerebral cortex is associated with the
formation of cored plaques and the deposition of
Aß40 in sporadic AD,27,29
does not
seem to be implicated. ApoE 4 allele frequency was similar in cases
with type 1 (12.5%) and type 2 (9.4%) histologies, neither differing
from population control data. Others50
have reported the
4 allele frequency to be normal in PS-1 AD.
However, because the type 1 profile has more
Aß42(43) and is associated with an earlier age
at onset and shorter disease duration, these observations have
important implications for the amyloid cascade
hypothesis.51
The data imply that increasing
Aß42(43) deposition accelerates the disease
process. Mutations favoring a heavy Aß42(43)
deposition are spread (in a strict linear sense) throughout the entire
protein length without displaying any obvious clustering. Indeed,
mutations associated with a heavy deposition can occur at, or adjacent
to, the same codon (eg, codon 139) as the lighter depositing ones. It
is therefore possible that even subtle differences in amino acid
substitution at any one codon might translate into more dramatic
alterations in the topology (folding characteristics) of the PS-1
protein and -secretase activity. It is possible that the variations
in mutational effect we have observed here result from more aggressive
mutations (ie, in terms of Aß42(43) deposition)
spatially clustering around the active site of PS-1. Furthermore, the
observation that some mutations are more aggressive than others has
clear implications for the transgenic modeling of PS-1 linked AD.
Transgenic mice containing PS-1 mutations, used in previous
studies8-11
have mutations that are relatively mild in
their Aß42(43) promoting ability compared to
some of the others reported here.
The molecular basis for the mutational clustering (ie, downstream of codon 200) for amyloid angiopathy is difficult to explain, and why this should differ from that pattern favoring Aß42(43) deposition as plaques is unclear. However, it is known that PS-1 is involved in Notch signaling.52,53 Transgenic mice lacking PS-1 or Notch, or mice homozygous for a processing-deficient allele of Notch 1, have altered vascularization of the yolk sac.54 Several other lines of evidence tie Notch signaling with vascular development. The Notch ligand Dll4 and Notch 4 are expressed in the vascular endothelium.55,56 Furthermore, mice deficient for both Notch 1 and Notch 4 have severe defects in angiogenic vascular remodeling, indicating an essential role for Notch signaling in vascular morphogenesis and remodeling.57 Moreover, mutations in Notch 3 result in CADASIL, a disease with a nonamyloid angiopathy.58 Collectively, these observations raise the possibility that PS-1 mutations associated with AD may act through two separate, although complimentary, mechanisms. Firstly, they increase the amount of Aß42(43) produced and deposited, and secondly, they effect Notch signaling resulting in a breakdown of the vascular epithelium. This, in turn, may result in plasma Aß (especially Aß40) leaking into brain tissue, seeding on pre-existing local deposits of Aß42(43), and producing the large plaques we have seen around such vessels and promoting the amyloid angiopathy itself. It should be noted that the proposed functionally important residues (ie, the aspartyl residues of the active site and the PS-1 cleavage site) are all located in the region of PS-1 where mutations are associated with severe amyloid angiopathy (ie, in type 2 histology cases). Nevertheless, whatever the ultimate reasons for the differing histological profiles in PS-1 AD, they do not contribute to disease progression because the type 2 cases are seemingly less aggressive, at least in terms of time of onset of illness and its duration.
The PS-1 gene consists of 11 exons and encodes a primary 2.7-kb
transcript that is translated into a 467-amino acid, 43- to 50-kd,
holoprotein.59,60
The holoprotein is normally processed
into 17-kd C-terminal fragments and 27- to 28-kd N-terminal fragments,
cleavage occurring at, or around, amino acid 298 (ie, within the
proximal part of the hydrophilic loop).28
Both C-terminal
fragments and N-terminal fragments of PS-1 form part of a larger,
stable complex that contains ß-catenin.61-65
It is
clear that very little holoprotein is normally present within the cell,
this being rapidly cleaved by a proposed protease, termed
presenilase.28
It has recently been shown that full-length
PS-1 is a zymogen and requires cleavage to activate -secretase
activity.23
However, it has also been demonstrated that
the delta 9 deletion mutated PS-1 (which cannot be cleaved) also
possesses -secretase activity.23
It remains to be
established whether any of the point mutations reported here also
confer -secretase activity on full length PS-1. Other recent
work66
implies that PS-1 mutations may affect the cleavage
of APP at its amino terminus, thereby modulating the activity of
ß-secretase.
In summary, therefore, it seems that in PS-1-linked AD there are two distinct histological profiles and that these result from the location of the particular mutation. Cases of type 1 histology show a greater Aß42(43) deposition and have an earlier age at onset and shorter disease duration. The extent of Aß deposition across cases does not relate to the mutational location in a strict linear sense, but cases showing high levels of deposition may cluster around (and be a marker of) the putative active site of PS-1. However, of great potential importance are the findings that the extent of amyloid angiopathy is related to mutational position, and this might involve a PS-1-mediated dysfunction of Notch signaling. Finally, we demonstrate that altered Aß processing in a cell culture model of mutant PS-1 correlates with the relevant pathological changes in humans.
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Acknowledgements |
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Footnotes |
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The Familial Alzheimer’s Disease Pathology Study Group Members are Juan Arango, Tom Bird, Christine Van Broeckhoven, William Brooks, Rosemary Brown, Nigel Cairns, Patrick Cras, David Ellison, Matti Haltia, Kunio Ii, Arne Jorgensen, Jillian Krill, Peter Lantos, Carol Lippa, Ralph Martins, David Nochlin, Daniel Pollen, Carlyn Rosenberg, Martin Rossor, and Takeshi Tabira.
Accepted for publication February 13, 2001.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-secretase activity in the detergent solubilized state. Proc Natl Acad Sci USA 2000, 97:6138-6143-secretase inhibitors directed to the active site covalently label presenilin 1. Nature 2000, 405:689-693[Medline]
-secretase is an intramembrane-cleaving aspartyl protease. Biochemistry 2000, 38:4720-4727
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