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PAPER
Association of a polymorphism of the transforming growth
factor-b1 gene with cerebral amyloid angiopathy
T Hamaguchi, S Okino, N Sodeyama, Y Itoh, A Takahashi, E Otomo, M Matsushita, H Mizusawa,
M Yamada
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
See end of article for
authors’ affiliations
. . . . . . . . . . . . . . . . . . . . . . .
Correspondence to:
Professor Masahito
Yamada, Department of
Neurology and
Neurobiology of Aging,
Kanazawa University
Graduate School of
Medical Science, 13-1,
Takara-machi, Kanazawa
920-8640, Japan;
m-yamada@med.
kanazawa-u.ac.jp
Received
12 December 2003
Revised version received
12 August 2004
Accepted 27 August 2004
. . . . . . . . . . . . . . . . . . . . . . .
J Neurol Neurosurg Psychiatry 2005;76:696–699. doi: 10.1136/jnnp.2003.034454
Background: A recent study showed that transforming growth factor-b1 (TGF-b1) induces amyloid-b
deposition in cerebral blood vessels and meninges of a transgenic mouse model of Alzheimer’s disease
(AD), and that TGF-b1 mRNA levels are correlated with cerebral amyloid angiopathy (CAA) in human AD
brains. A T/C polymorphism at codon 10 in exon 1 of the TGF-b1 gene has been reported to be
associated with the serum TGF-b1 concentration. We investigated whether the TGF-b1 polymorphism is
associated with the risk of CAA.
Methods: The association between the severity of CAA and the T/C polymorphism at codon 10 in exon 1
of the TGF-b1 was investigated in 167 elderly Japanese autopsy cases, including 73 patients with AD. The
apolipoprotein E (APOE) genotype was also determined.
Results: The genotypes (TT/ TC/ CC) were associated with the severity of CAA significantly in all patients
(p = 0.0026), in non-AD patients (p = 0.011), and APOE non-e4 carriers (p = 0.0099), but not in AD
patients or APOE e4 carriers. The number of the T alleles positively correlated with the severity of CAA in
all patients (p = 0.0011), non-AD patients (p = 0.0026 ), and APOE non-e4 carriers (p = 0.0028), but
not in AD patients or APOE e4 carriers. The polymorphism was not significantly associated with AD.
Conclusions: Our results suggest that the polymorphism in TGF-b1 is associated with the severity of CAA,
especially in non-AD patients and APOE non-e4 carriers.
C
erebral amyloid angiopathy (CAA) is a cerebrovascular
amyloid deposition related to intracerebral haemorrhage and other cerebrovascular disorders.1 2 CAA is
commonly found in the elderly as well as in Alzheimer’s
disease (AD),1 2 and some genetic risk factors for AD have
been reported to be associated with sporadic CAA.3–10 The e4
allele of the apolipoprotein E (apoE) gene (APOE), an
established risk factor of AD, has been suggested to be a
risk factor of CAA,3 4 although this was not evident in some
populations5 6 and the APOE e2 allele may be associated with
CAA-related haemorrhage.7 We previously reported that the
polymorphisms in the presenilin-1, a1-antichymotrypsin, and
neprilysin genes may be associated with sporadic CAA.8–10 AD
and CAA share risk factors in the common pathogenetic
process of amyloid b protein (Ab) deposition.
The multifunctional cytokine transforming growth factorb1 (TGF-b1) is a potent regulator of injury and inflammatory
responses in the central nervous system11 and has been
implicated in cerebral amyloid deposition12–14 and AD
pathogenesis.11 15 16 Cerebral TGF-b1 mRNA levels are correlated positively with the extent of amyloid deposition in
cerebral blood vessels in AD cases.12 Astroglial overproduction
of TGF-b1 in aged transgenic mice expressing the human
b-amyloid precursor protein (hAPP) promotes the deposition
of human Ab in cerebral vessels.12 In hAPP/TGF-b1 bigenic
mice, in spite of its amyloidogenic effects on the cerebral
vasculature, TGF-b1 strongly reduces the overall cerebral Ab
load by inhibiting the formation of neuritic plaques in the
brain parenchyma.14
The levels of TGF-b1 in the central nervous system are
reportedly increased greatly in response to ischaemic,
exciotoxic, and traumatic brain injury.17–21 Eight polymorphisms of the TGF-b1 gene (TGF-b1) located to 19q13.1–13.322
have been detected.23 24 Although the details of TGF-b1
expression are still unclear, polymorphisms of the TGF-b1
may play a role in the control of the TGF-b1 level in plasma.24–26
Recently, one of these polymorphisms, a T/C transition at
nucleotide 29 in the region encoding the signal sequence,
which results in a Leu/Pro substitution at amino acid 10,
has been reported to be associated with the serum
concentration or production of TGF-b124 25 27 and with
diseases such as osteoporosis,25 myocardial infarction,24
rheumatoid arthritis,28 and invasive breast cancer.27
In the present study, we investigated whether the T/C
polymorphism at codon 10 in exon 1 of the TGF-b1 is
associated with CAA in elderly individuals.
SUBJECT AND METHODS
Patients
We studied 167 Japanese patients (age 62–104 years;
mean ¡ SD, 86.0 ¡ 7.8 years). They were consecutive
autopsy cases in a large geriatric hospital, excluding cases
in which brain samples could not be obtained for study and
cases of neurodegenerative diseases other than AD. Consent
was obtained from all families of participants at autopsy. This
study project was approved by the ethics committee of each
institution. The 167 patients included 73 patients with
sporadic AD, in which the neuropathological findings
satisfied the criteria of the Consortium to Establish a
Registry for Alzheimer’s Disease,29 and 94 subjects without
AD or other neurodegenerative disorders. All the AD patients
clinically showed dementia on the basis of the criteria of
American Psychiatric Association.30 There was no significant
difference in the age at death between AD (86.1 ¡ 8.0) and
non-AD (86.0 ¡ 7.7) groups. No familial cases of AD or CAA
were included in this series.
Abbreviations: Ab, amyloid b protein; AD, Alzheimer’s disease;
APOE, apolipoprotein E; CAA, cerebral amyloid angiopathy; hAPP,
human b-amyloid precursor protein; PCR, polymerase chain reaction;
TGF-b1, transforming growth factor-b1
696
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Neuropathological evaluation of CAA
Congophilic deposits with green birefringence under
polarised light were identified as amyloid deposits. The
cerebrovascular amyloid deposits were immunohistochemically confirmed to be Ab. Using a large section of the occipital
lobe (about 464 cm in size), the numbers of meningeal and
cortical vessels (small arteries and arterioles) with and
without amyloid deposits were counted in the whole section,
and the percentage of amyloid-laden vessels was calculated
(= CAA count). We examined the occipital lobe because it
was the most frequently affected by CAA in our previous
study in both AD and non-AD cases31 and seemed suitable for
detecting CAA of very slight degree. The quantification was
performed without knowledge of the TGF-b1 or APOE
genotypes. Severe vascular wall involvement was commonly
found in patients with high CAA counts, and some of them
presented with secondary degenerative changes — that is,
CAA associated vasculopathies. However, we did not use data
of such morphological changes because it was difficult to
evaluate totally and quantitatively the extent of amyloid
involvement of each blood vessel, and only a small number of
patients with CAA associated vasculopathies were included in
this series. We used only the CAA counts for our statistical
analysis to represent the severity of CAA.
Identification of the TGF-b1 polymorphism
Genomic DNA was isolated from the frozen brain tissue of all
patients using a standard phenolchlorophorm extraction
procedure. TGF-b1 genotype was determined by a direct
sequence method as previously described.23 Briefly, the first
exon of the TGF-b1 was amplified by polymerase chain
reaction (PCR) with sense (59-TCCTACCTTTTGCCGGGAGAC39) and antisense (59-GTTGTGGGTTTCCACCATTAG-39) primers. The PCR products were sequenced with a fluorescencebased automated DNA sequencer (Prism 310; Applied
Biosystems, CA, USA). The APOE genotype was also
determined as previously described.5
Statistical analysis
Comparison of the distributions of the AD and non-AD
patients over the TGF-b1 genotype categories (TT, TC, and
CC) were performed using a x2 test.
CAA counts were compared between the TGF-b1 genotypes
(TT, TC, and CC) in AD, non-AD, and all patients. Because the
counts did not follow a normal distribution in any group, we
used the Kruskal-Wallis test for the comparison as a nonparametric test. Similar analyses were performed according
to the subgroups of APOE e4 status. We also used the MannWhitney U test to compare CAA counts between AD and nonAD patients. The correlation between the number of T allele
and CAA counts was examined with Spearman’s rank
correlation analysis.
Statistical significance was defined as p,0.05. The
statistical analyses were performed using StatView J-7.5
(Abacus Concepts, Berkeley, CA, USA).
RESULTS
Among the 167 patients examined, TT, TC, and CC genotypes
of the TGF-b1 polymorphism were found in 47, 77, and 43
individuals, respectively (0.51 in T-type allele frequency and
0.49 in C-type allele frequency). Age did not differ
significantly between the genotypes. The distribution of
the TGF-b1 genotype in AD and non-AD is shown in
Table 1. The TGF-b1 genotype was not significantly different
between AD and non-AD subjects. There was a strong
association between AD and the APOE e4 allele in this
population (p,0.0001) as we previously reported in a smaller
number of samples.32
Sixty two (84.9%) of 73 AD patients and 29 (30.9%) of 94
non-AD patients were affected by CAA. Average values of
CAA counts and numbers of patients with CAA in the TGF-b1
genotypes are shown in Table 2. Average values of CAA
counts were significantly different between TT, TC, and CC
genotypes in all patients (p = 0.0026) and in the non-AD
patients (p = 0.011), but not in the AD patients. When the
patients were categorised by APOE e4 status, the average CAA
count was significantly different between the genotypes in
the non-e4 carriers (p = 0.0099) but not in the e4 carriers
(Table 2). In this population, the CAA count was significantly
higher in the AD patients than in the non-AD patients
(p,0.0001), and was higher in the APOE e4 carriers than in
the APOE non-e4 carriers (p = 0.002) (Table 2).
The number of T alleles in the TGF-b1 polymorphism
showed a significant positive correlation with the CAA count
in all patients (r = 0.255, p = 0.0011), non-AD patients
(r = 0.316, p = 0.0033), and APOE non-e4 carriers
(r = 0.272, p = 0.0028), but not in the AD patients or e4
carriers.
Table 1 Distribution of the TGF-b1 genotypes in
Alzheimer’s disease (AD) and non-AD
AD (n = 73) Non-AD (n = 94) p
Genotype, n (%)
TT 23 (31.5%) 24 (25.5%)
TC 36 (49.3%) 41 (43.6%) NS
CC 14 (19.2%) 29 (30.9%)
*Statistical difference in the TGF-b1 genotypes between AD and non-AD
by x2 test.
Table 2 Average cerebral amyloid angiopathy (CAA) counts in the TGF-b1 genotype
TGF-b1 genotype
Total p*TT TC CC
Total 22.6 ¡ 4.3 (33/47) 21.5 ¡ 3.4 (44/77) 11.8 ¡ 4.2 (14/43) 19.3 ¡ 2.3 (91/167) 0.0026
AD or non-AD
AD 27.1 ¡ 5.7 (21/23) 32.2 ¡ 5.1 (31/36) 28.9 ¡ 9.7 (10/14) 29.9 ¡ 3.6 (62/73) NS
Non-AD 18.3 ¡ 6.3 (12/24) 11.7 ¡ 4.0 (13/41) 3.6 ¡ 3.3 (4/29) 10.9 ¡ 2.6 (29/94) 0.011
Status of APOE
e4 (+) 23.1 ¡ 5.9 (12/14) 27.1 ¡ 6.1 (18/22) 21.1 ¡ 14.3 (5/7) 24.8 ¡ 4.3` (35/43) NS
e4 (2) 22.4 ¡ 5.6 (21/33) 19.2 ¡ 4.1 (26/55) 10.0 ¡ 4.3 (9/36) 17.4 ¡ 2.7 (56/124) 0.0099
Values are means ¡ SE. Values in parentheses are numbers of CAA patients/total patients. Average CAA counts are calculated by using the data from total
patients.
*Statistical difference in CAA counts between the TGF-b1 genotypes by Kruskal-Wallis test; p,0.0001 (AD v non-AD) by the Mann-Whitney U test; `p = 0.002
(e4 (+) v e4 (2)) by the Mann-Whitney U test. AD, Alzheimer’s disease; APOE, apolipoprotein E; TGF-b1, transforming growth factor-b1.
TGF-b1 polymorphism and CAA 697
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DISCUSSION
Our results revealed that the genotypes and number of T
alleles of the T/C polymorphism at codon 10 in exon 1 of the
TGF-b1 were associated with the severity of CAA. An increase
in the number of T alleles in the TGF-b1 polymorphism may
be a risk factor of CAA in the elderly, especially for non-AD
patients and APOE non-e4 carriers.
TGF-b1 may be related to the pathogenesis of AD and
CAA.11 12 14–16 It has been reported that cerebral TGF-b1 levels
are higher in AD patients than in non-demented controls,15 16
and that TGF-b1 is present in senile plaques and is
overexpressed in AD.11 It has been shown in recent studies12 14
that increased production of TGF-b1 promotes deposition of
Ab in cerebral blood vessels, but reduces plaque formation in
the brain parenchyma in AD patients or AD mice models. By
contrast, TGF-b1 has been reported to potentiate Ab
generation in astrocytes and transgenic mice promoting Ab
deposition in the brain.33 TGF-b1 may have complex effects
on the expression and processing of APP, Ab clearance from
the brain, and cerebrovascular Ab deposition, probably
through activation of astrocytes and microglias.14 33
Association of TGF-b1 polymorphisms with AD has been
studied, including the polymorphisms at 2800, 2509, codon
263 in exon 5, and +25 in the TGF-b1.34 35 A weak association
of the 2509 T allele with AD was reported in an American
population;34 however, there was no association between the
2509 polymorphism and AD in another study.35 The other
polymorphisms of TGF-b1 were not associated with AD.34 35 In
this study, we investigated the association of the T/C
polymorphism at codon 10 in exon 1 of the TGF-b1 with
AD for the first time, and failed to find any significant
association. Therefore, the association of the TGF-b1 polymorphism with CAA would be independent of AD, although
there is a close relation between CAA and AD.36
The T/C polymorphism of the TGF-b1 results in the Leu/Pro
substitution of TGF-b1, which is located in the 29-residue
signal peptide sequence.24 25 The TGF-b1 polymorphism may
affect the function of the signal peptide, perhaps influencing
intracellular trafficking or export efficiency of the preproprotein, and the TGF-b1 genotypes may be associated with the
production of this protein. The T allele of the TGF-b1
polymorphism has been reported to be associated with
reduced levels of TGF-b1 proteins in serum.24 25 In transfection experiments with HeLa cells, the signal peptide with Pro
at residue 10 encoded by the C allele causes an increase in
secretion of TGF-b1 compared with the Leu form encoded by
the T allele.27
If the T allele is associated with reduced levels of TGF-b1 in
the brain as well as in serum,24 25 our data suggest that
reduced TGF-b1 levels may be associated with increased
severity of CAA. This is inconsistent with the reports that
TGF-b1 would promote CAA in AD patients and AD mice
models.12 14 This discrepancy may be related to the difference
in the role of TGF-b1 for cerebrovascular amyloid deposition
between AD and non-AD patients, or the difference in the
role of this polymorphism in expression of TGF-b1 between
systemic circulation and brain. We do not have any definite
explanation for this discrepancy because we have no data on
the TGF-b1 concentration in the central nervous system from
these patients. Our results indicate an important role of
TGF-b1 in CAA, requiring further study to elucidate the
pathomechanism.
CAA-related cerebrovascular disorders include lobar cerebral and cerebellar haemorrhages, leucoencephalopathy, and
cortical small haemorrhage.2 Patients with asymptomatic
CAA may develop cerebral haemorrhages following antithrombotic or anticoagulation treatment against thromboembolic disorders37 38 or Ab immunotherapy against AD.39
Because there are no definitive biological markers or imaging
technologies for definite diagnosis of the CAA, except for
pathological examination of the brain, further development
of tests to evaluate risk of CAA is necessary. AD and APOE e4
have been reported to be independent risk factors of CAA,
but CAA is also observed in non-AD or APOE non-e4
carriers.1–10 31 35 Interestingly, the polymorphism of TGF-b1 is
a risk factor of CAA especially in non-AD or APOE non-e4
carriers, which may contribute to prediction of CAA in such
cases.
The current study has limitations; our sample population
was relatively small and obtained from an autopsy series in a
geriatric hospital. Our results warrant further study with a
larger sample size from populations with various ethnic
backgrounds.
In conclusion, our results suggest that the T/C polymorphism at codon 10 in exon 1 of the TGF-b1 would be associated
with the severity of CAA, especially in non-AD or APOE none4 carriers.
ACKNOWLEDGEMENTS
We thank Dr J Adachi (The Institute of Statistical Mathematics) for
his useful comments on our statistical analysis. The study was
supported by grants from the Amyloidosis Research Committee
(to MY) and the Research Committee of Genetic Analyses of
Cerebrovascular Disorders (to MY), the Ministry of Health, Labour
and Welfare, Japan, and by a Grant-in-Aid for Scientific Research (to
MY) from the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
Authors’ affiliations
. . . . . . . . . . . . . . . . . . . . .
T Hamaguchi, S Okino, M Yamada, Department of Neurology and
Neurobiology of Aging, Kanazawa University Graduate School of
Medical Science, Kanazawa, Japan
N Sodeyama, H Mizusawa, Department of Neurology and
Neurological Science, Tokyo Medical and Dental University, Tokyo,
Japan
Y Itoh, E Otomo, Department of Internal Medicine, Yokufukai Geriatric
Hospital, Tokyo, Japan
A Takahashi, Organ and Function Pathology Division, Yokufukai
Geriatric Hospital, Tokyo, Japan
M Matsushita, Department of Neuropathology, Tokyo Institute of
Psychiatry, Tokyo, Japan
Competing interests: none declared
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