Nature,
Год журнала:
2023,
Номер
618(7964), С. 349 - 357
Опубликована: Май 31, 2023
The
incidence
of
Alzheimer's
disease
(AD),
the
leading
cause
dementia,
increases
rapidly
with
age,
but
why
age
constitutes
main
risk
factor
is
still
poorly
understood.
Brain
ageing
affects
oligodendrocytes
and
structural
integrity
myelin
sheaths1,
latter
which
associated
secondary
neuroinflammation2,3.
As
support
axonal
energy
metabolism
neuronal
health4-7,
we
hypothesized
that
loss
could
be
an
upstream
for
amyloid-β
(Aβ)
deposition,
central
neuropathological
hallmark
AD.
Here
identify
genetic
pathways
dysfunction
demyelinating
injuries
as
potent
drivers
amyloid
deposition
in
mouse
models
Mechanistically,
causes
accumulation
Aβ-producing
machinery
within
swellings
cleavage
cortical
precursor
protein.
Suprisingly,
AD
mice
dysfunctional
lack
plaque-corralling
microglia
despite
overall
increase
their
numbers.
Bulk
single-cell
transcriptomics
defects
show
there
a
concomitant
induction
highly
similar
distinct
disease-associated
signatures
specific
to
damage
plaques,
respectively.
Despite
successful
induction,
(DAM)
usually
clear
plaques
are
apparently
distracted
nearby
damage.
Our
data
suggest
working
model
whereby
age-dependent
promote
Aβ
plaque
formation
directly
indirectly
therefore
factor.
Improving
oligodendrocyte
health
promising
target
delay
development
slow
progression
Frontiers in Immunology,
Год журнала:
2019,
Номер
10
Опубликована: Авг. 30, 2019
Human
monocytes
are
divided
in
three
major
populations;
classical
(CD14+CD16-),
non-classical
(CD14dimCD16+),
and
intermediate
(CD14+CD16+).
Each
of
these
subsets
is
distinguished
from
each
other
by
the
expression
distinct
surface
markers
their
functions
homeostasis
disease.
In
this
review,
we
discuss
most
up-to-date
phenotypic
classification
human
that
has
been
greatly
aided
application
novel
single-cell
transcriptomic
mass
cytometry
technologies.
Furthermore,
shed
light
on
role
plastic
immune
cells
already
recognized
emerging
chronic
diseases,
such
as
obesity,
atherosclerosis,
obstructive
pulmonary
disease,
lung
fibrosis,
cancer,
Alzheimer's
Our
aim
to
provide
an
insight
into
contribution
progression
diseases
highlight
candidacy
potential
therapeutic
cell
targets.
Nature Communications,
Год журнала:
2019,
Номер
10(1)
Опубликована: Авг. 21, 2019
Abstract
Many
risk
genes
for
the
development
of
Alzheimer’s
disease
(AD)
are
exclusively
or
highly
expressed
in
myeloid
cells.
Microglia
dependent
on
colony-stimulating
factor
1
receptor
(CSF1R)
signaling
their
survival.
We
designed
and
synthesized
a
selective
brain-penetrant
CSF1R
inhibitor
(PLX5622)
allowing
extended
specific
microglial
elimination,
preceding
during
pathology
development.
find
that
5xFAD
mouse
model
AD,
plaques
fail
to
form
parenchymal
space
following
depletion,
except
areas
containing
surviving
microglia.
Instead,
Aβ
deposits
cortical
blood
vessels
reminiscent
cerebral
amyloid
angiopathy.
Altered
gene
expression
hippocampus
is
also
reversed
by
absence
Transcriptional
analyses
residual
plaque-forming
microglia
show
they
exhibit
disease-associated
profile.
Collectively,
we
describe
structure,
formulation,
efficacy
PLX5622,
which
allows
sustained
depletion
identify
roles
initiating
plaque
pathogenesis.
Frontiers in Pharmacology,
Год журнала:
2019,
Номер
10
Опубликована: Сен. 12, 2019
Neurodegenerative
diseases
share
the
fact
that
they
derive
from
altered
proteins
undergo
an
unfolding
process
followed
by
formation
of
-structures,
and
a
pathological
tendency
to
self-aggregate
in
neuronal
cells.
This
is
characteristic
tau
protein
Alzheimer´s
disease
several
tauopathies
associated
unfolding,
synuclein
Parkinson
huntingtin
Huntington
disease.
Usually
self-aggregation
products
are
toxic
these
cells,
toxicity
spreads
all
over
different
brain
areas.
We
have
postulated
events
molecular
alterations
trigger
neurodegenerative
disorders.
Most
interestingly,
occur
as
result
neuroinflammatory
cascades
involving
cross-talks
between
glial
cells
neurons
consequence
activation
microglia
astrocytes.
The
model
we
hypothesized
for
disease,
involve
damage
signals
promote
activation,
NFβ
synthesis
release
proinflammatory
cytokines
such
TNF-,
IL1,
IL-6,
IL-12
affects
receptors
with
overactivation
kinases.
These
patterns
can
be
applied
In
this
context,
involvement
innate
immunity
seems
major
paradigm
pathogenesis
diseases.
important
element
search
potential
therapeutic
approaches
