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Anti-angiogenic activity of the mutant Dutch A(beta) peptide on human brain microvascular endothelial cells.
[hereditary cerebral hemorrhage with amyloidosis]
Cerebral
amyloid
angiopathy
is
a
common
pathological
feature
of
patients
with
Alzheimer
's
disease
(
AD
)
and
it
is
also
the
hallmark
of
individuals
with
a
rare
autosomal
dominant
disorder
known
as
hereditary
cerebral
hemorrhage
with
amyloidosis
-
Dutch
type
.
We
have
shown
previously
that
wild
type
A
(
beta
)
peptides
are
anti-angiogenic
both
in
vitro
and
in
vivo
and
could
contribute
to
the
compromised
cerebrovascular
architecture
observed
in
AD
.
In
the
present
study
,
we
investigated
the
potential
anti-angiogenic
activity
of
the
Dutch
A
(
beta
)
(
1
-
40
)
(
E
22
Q
)
peptide
.
We
show
that
compared
to
wild
type
A
(
beta
)
,
freshly
solubilized
Dutch
A
(
beta
)
peptide
more
potently
inhibits
the
formation
of
capillary
structures
induced
by
plating
human
brain
microvascular
endothelial
cells
onto
a
reconstituted
basement
membrane
.
Aggregated
/
fibrillar
preparations
of
wild
type
A
(
beta
)
and
Dutch
A
(
beta
)
do
not
appear
to
be
anti-angiogenic
in
this
assay
.
The
stronger
anti-angiogenic
activity
of
the
Dutch
A
(
beta
)
compared
to
wild
type
A
(
beta
)
appears
to
be
related
to
the
increased
formation
of
low
molecular
weight
A
(
beta
)
oligomers
in
the
culture
medium
surrounding
human
brain
microvascular
endothelial
cells
.
Using
oligonucleotide
microarray
analysis
of
human
brain
microvascular
endothelial
cells
,
followed
by
a
genome-scale
computational
analysis
with
the
Ingenuity
Pathways
Knowledge
Base
,
networks
of
genes
affected
by
an
anti-angiogenic
dose
of
Dutch
A
(
beta
)
were
identified
.
This
analysis
highlights
that
several
biological
networks
involved
in
angiogenesis
,
tumorigenesis
,
atherosclerosis
,
cellular
migration
and
proliferation
are
disrupted
in
human
brain
microvascular
endothelial
cells
exposed
to
Dutch
A
(
beta
)
.
Altogether
,
these
data
provide
new
molecular
clues
regarding
the
pathological
activity
of
Dutch
A
(
beta
)
peptide
in
the
cerebrovasculature
.
Diseases
Validation
Diseases presenting
"atherosclerosis"
symptom
achondroplasia
acute rheumatic fever
adrenal incidentaloma
alexander disease
aromatase deficiency
benign recurrent intrahepatic cholestasis
cadasil
classical phenylketonuria
congenital adrenal hyperplasia
congenital toxoplasmosis
cushing syndrome
erdheim-chester disease
familial mediterranean fever
harlequin ichthyosis
hereditary cerebral hemorrhage with amyloidosis
inclusion body myositis
sneddon syndrome
werner syndrome
zellweger syndrome
This symptom has already been validated