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Charge alterations of E22 enhance the pathogenic properties of the amyloid beta-protein.
[hereditary cerebral hemorrhage with amyloidosis]
Cerebral
amyloid
angiopathy
(
CAA
)
due
to
amyloid
beta
-protein
(
Abeta
)
is
a
key
pathological
feature
of
patients
with
Alzheimer
's
disease
and
hereditary
cerebral
hemorrhage
with
amyloidosis
,
Dutch
-
type
(
HCHWA-D
)
.
The
CAA
in
these
disorders
is
characterized
by
deposition
of
Abeta
in
the
smooth
muscle
cells
within
the
cerebral
vessel
wall
.
Recently
,
a
new
mutation
in
Abeta
,
E
22
K
,
was
identified
in
several
Italian
families
that
,
like
HCHWA-D
,
is
associated
with
CAA
and
hemorrhagic
stroke
.
These
two
similar
disorders
,
stemming
from
amino
acid
substitutions
at
position
22
of
Abeta
,
implicate
the
importance
of
this
site
in
the
pathology
of
HCHWA
.
Previously
we
showed
that
HCHWA-D
Abeta
(
1
-
40
)
containing
the
E
22
Q
substitution
induces
robust
pathologic
responses
in
cultured
human
cerebrovascular
smooth
muscle
cells
(
HCSM
cells
)
,
including
highly
elevated
levels
of
cell-associated
Abeta
precursor
(
AbetaPP
)
and
cell
death
.
In
the
present
study
,
a
series
of
E
22
mutant
Abeta
(
1
-
40
)
peptides
were
synthesized
,
and
their
pathogenic
properties
toward
cultured
HCSM
cells
were
evaluated
.
Quantitative
fluorescence
analyses
showed
that
mutant
Abeta
(
1
-
40
)
peptides
either
containing
a
loss
of
charge
(
E
22
Q
and
E
22
A
)
or
a
change
of
charge
(
E
22
K
)
bind
to
the
surface
of
HCSM
cells
and
form
amyloid
fibrils
.
Similarly
,
this
same
group
of
E
22
mutant
Abeta
(
1
-
40
)
peptides
caused
enhanced
pathologic
responses
in
HCSM
cells
.
In
contrast
,
wild-
type
E
22
or
the
charge-preserving
E
22
D
Abeta
(
1
-
40
)
peptides
were
devoid
of
any
of
these
pathogenic
properties
.
These
data
suggest
that
a
change
or
loss
of
charge
at
position
22
of
Abeta
enhances
the
pathogenic
effects
of
the
peptide
toward
HCSM
cells
and
may
contribute
to
the
pathogenesis
of
the
phenotypically
related
HCHWA
disorders
.
Diseases
Validation
Diseases presenting
"loss of charge"
symptom
hereditary cerebral hemorrhage with amyloidosis
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