Proceedings of the National Academy of Sciences,
Год журнала:
2016,
Номер
113(19)
Опубликована: Апрель 18, 2016
Significance
Dysfunction
of
the
innate
immune
system
is
involved
in
pathogenesis
Alzheimer’s
disease
(AD);
however,
pathophysiological
mechanisms
underlying
these
dysfunctions
are
unclear.
Here
we
report
that
stimulation
IL-33/ST2
signaling
rescues
memory
deficits
and
reduces
accumulation
β-amyloid
APP/PS1
mice
exhibit
select
pathologies
associated
with
AD.
Although
impaired
early
progression
AD,
IL-33
injection
contextual
mice.
skews
microglia
toward
an
alternative
activation
state
enhanced
Aβ
phagocytic
capacity
elevated
antiinflammatory
gene
expression,
which
results
a
decreased
proinflammatory
response
brain.
Thus,
this
study
suggests
can
be
developed
as
new
therapeutic
intervention
for
Cold Spring Harbor Perspectives in Medicine,
Год журнала:
2012,
Номер
2(6), С. a006262 - a006262
Опубликована: Фев. 21, 2012
Colin
L.
Masters1
and
Dennis
J.
Selkoe2
The
Mental
Health
Research
Institute,
University
of
Melbourne,
Parkville
3010,
Australia
Center
for
Neurologic
Diseases,
Harvard
Medical
School
Brigham
Women's
Hospital,
Boston,
Massachusetts
02115
Correspondence:
c.masters{at}unimelb.edu.au
Cold Spring Harbor Perspectives in Medicine,
Год журнала:
2011,
Номер
2(1), С. a006304 - a006304
Опубликована: Ноя. 8, 2011
Presenilins
were
first
discovered
as
sites
of
missense
mutations
responsible
for
early-onset
Alzheimer
disease
(AD).
The
encoded
multipass
membrane
proteins
subsequently
found
to
be
the
catalytic
components
γ-secretases,
membrane-embedded
aspartyl
protease
complexes
generating
carboxyl
terminus
amyloid
β-protein
(Aβ)
from
protein
precursor
(APP).
complex
also
cleaves
a
variety
other
type
I
integral
proteins,
most
notably
Notch
receptor,
signaling
which
is
involved
in
many
cell
differentiation
events.
Although
γ-secretase
top
target
developing
disease-modifying
AD
therapeutics,
interference
with
should
avoided.
Compounds
that
alter
Aβ
production
by
without
affecting
proteolysis
and
have
been
identified
are
currently
at
various
stages
drug
development
pipeline.
The Journal of Experimental Medicine,
Год журнала:
2020,
Номер
217(9)
Опубликована: Июнь 24, 2020
TREM2
is
a
receptor
for
lipids
expressed
in
microglia.
The
R47H
variant
of
human
impairs
ligand
binding
and
increases
Alzheimer's
disease
(AD)
risk.
In
mouse
models
amyloid
β
(Aβ)
accumulation,
defective
function
affects
microglial
response
to
Aβ
plaques,
exacerbating
tissue
damage,
whereas
overexpression
attenuates
pathology.
Thus,
AD
may
benefit
from
activation.
Here,
we
examined
the
impact
an
anti-human
agonistic
mAb,
AL002c,
model
expressing
either
common
(CV)
or
TREM2.
Single-cell
RNA-seq
microglia
after
acute
systemic
administration
AL002c
showed
induction
proliferation
both
CV-
R47H-transgenic
mice.
Prolonged
reduced
filamentous
plaques
neurite
dystrophy,
impacted
behavior,
tempered
inflammatory
response.
We
further
that
safe
well
tolerated
first-in-human
phase
I
clinical
trial
engages
based
on
cerebrospinal
fluid
biomarkers.
conclude
AL002
promising
candidate
therapy.
Journal of Neurochemistry,
Год журнала:
2016,
Номер
139(S2), С. 237 - 252
Опубликована: Июнь 3, 2016
Abstract
The
first
description
of
Alzheimer's
disease
(
AD
)
was
made
in
1907
by
Alois
Alzheimer
Allgemeine
Zeitschrift
fur
Psyciatrie
und
Psychisch‐Gerichtliche
Medizin
64,
3,
1907),
although
other
contemporary
physicians
had
similar,
and
rather
more
complete,
assessments
the
neuropathological
changes
present
brain
(Fischer,
Monatsschr
Psychiat
Neurol
22,
17,
1907).
Our
knowledge
has
increased
dramatically
continues
to
accelerate.
This
year
is
25
years
after
publication
a
series
papers
that,
various
ways,
articulated
amyloid
cascade
hypothesis
ACH
for
(Beyreuther
Masters,
Brain
Pathol
1,
241–251,
1991;
Hardy
Allsop,
Trends
Pharmacol
Sci
12,
383–388,
Selkoe,
Neuron
6,
487–498,
Higgins,
Science
256,
184–185,
1992).
review
will
cover
some
familiar
territory,
but
we
shall
also
place
into
wider
context,
compare
it
with
hypotheses
,
explore
evolution
encompass
new
findings,
determine,
irrespective
merits
itself,
whether
been
useful
research
field,
both
academia
industry.
Finally,
how
led
number
therapeutic
approaches,
all
which
have,
date,
failed
reach
their
primary
efficacy
end‐points
clinical
trials
reflect
upon
what
future
may
hold.
image
We
(ACH)
that
have
posited
explain
initiation
progression
disease.
document
data
support
ACH,
its
deficiencies.
list
recent
failures
amyloidocentric
drugs
anticipate
results
approaches
deliver.
article
part
60th
Anniversary
special
issue
.
