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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
.
