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Aggregation and cytotoxic properties towards cultured cerebrovascular cells of Dutch-mutated Abeta40 (DAbeta(1-40)) are modulated by sulfate moieties of heparin.
[hereditary cerebral hemorrhage with amyloidosis]
Glycosaminoglycans
(
GAGs
)
,
in
particular
as
part
of
heparan
sulfate
proteoglycans
,
are
associated
with
cerebral
amyloid
angiopathy
(
CAA
)
.
Similarly
,
GAGs
are
also
associated
with
the
severe
CAA
found
in
patients
suffering
from
hereditary
cerebral
hemorrhage
with
amyloidosis
of
the
Dutch
type
(
HCHWA-D
)
,
where
the
amyloid
beta
(
Abeta
)
peptide
contains
the
Dutch
mutation
(
DAbeta
(
1
-
40
)
)
.
This
suggests
a
role
for
GAGs
in
vascular
Abeta
aggregation
.
It
was
the
aim
of
this
study
to
investigate
the
effect
of
different
GAGs
(
heparin
,
chondroitin
sulfate
,
heparan
sulfate
)
,
the
macromolecule
dextran
sulfate
and
,
using
desulfated
heparins
,
the
role
of
GAG
sulfate
moieties
on
the
in
vitro
aggregation
of
CAA-associated
DAbeta
(
1
-
40
)
and
on
DAbeta
(
1
-
40
)
-
induced
toxicity
of
cultured
cerebrovascular
cells
.
We
also
aimed
to
study
the
in
vivo
distribution
of
various
sulfated
heparan
sulfate
GAG
epitopes
in
CAA
.
Of
all
GAGs
tested
,
heparin
was
the
strongest
inducer
of
aggregation
of
DAbeta
(
1
-
40
)
in
the
different
aggregation
assays
,
with
both
heparin
and
heparan
sulfate
reducing
Abeta-induced
cellular
toxicity
.
Furthermore
,
(
partial
)
removal
of
the
sulfate
moieties
of
heparin
partially
abolished
the
effects
of
heparin
on
aggregation
and
cellular
toxicity
,
suggesting
an
essential
role
for
the
sulfate
moieties
in
heparin
.
Finally
,
we
demonstrated
the
in
vivo
association
of
sulfated
heparan
sulfate
(
HS
)
GAGs
with
CAA
.
We
conclude
that
sulfate
moieties
within
GAGs
,
like
heparin
and
HS
,
have
an
important
role
in
Abeta
aggregation
in
CAA
and
in
Abeta-mediated
toxicity
of
cerebrovascular
cells
.
Diseases
Validation
Diseases presenting
"cerebral amyloid angiopathy"
symptom
cadasil
hereditary cerebral hemorrhage with amyloidosis
This symptom has already been validated