Science Advances,
Journal Year:
2023,
Volume and Issue:
9(21)
Published: May 26, 2023
Sepsis-associated
encephalopathy
(SAE)
is
a
severe
and
frequent
complication
of
sepsis
causing
delirium,
coma,
long-term
cognitive
dysfunction.
We
identified
microglia
C1q
complement
activation
in
hippocampal
autopsy
tissue
patients
with
increased
C1q-mediated
synaptic
pruning
murine
polymicrobial
model.
Unbiased
transcriptomics
isolated
derived
from
septic
mice
revealed
an
involvement
the
innate
immune
system,
activation,
up-regulation
lysosomal
pathways
during
SAE
parallel
to
neuronal
damage.
Microglial
engulfment
C1q-tagged
synapses
could
be
prevented
by
stereotactic
intrahippocampal
injection
specific
C1q-blocking
antibody.
Pharmacologically
targeting
PLX5622,
CSF1-R
inhibitor,
reduced
levels
number
synapses,
protected
damage
synapse
loss,
improved
neurocognitive
outcome.
Thus,
we
complement-dependent
as
crucial
pathomechanism
for
development
defects
SAE.
Nature Neuroscience,
Journal Year:
2022,
Volume and Issue:
26(1), P. 12 - 26
Published: Dec. 19, 2022
Iron
dysregulation
has
been
implicated
in
multiple
neurodegenerative
diseases,
including
Parkinson's
disease
(PD).
Iron-loaded
microglia
are
frequently
found
affected
brain
regions,
but
how
iron
accumulation
influences
physiology
and
contributes
to
neurodegeneration
is
poorly
understood.
Here
we
show
that
human
induced
pluripotent
stem
cell-derived
grown
a
tri-culture
system
highly
responsive
susceptible
ferroptosis,
an
iron-dependent
form
of
cell
death.
Furthermore,
overload
causes
marked
shift
the
microglial
transcriptional
state
overlaps
with
transcriptomic
signature
PD
postmortem
microglia.
Our
data
also
this
response
neurodegeneration,
as
removal
from
substantially
delayed
iron-induced
neurotoxicity.
To
elucidate
mechanisms
regulating
microglia,
performed
genome-wide
CRISPR
screen
identified
novel
regulators
vesicle
trafficking
gene
SEC24B.
These
suggest
critical
role
for
ferroptosis
neurodegeneration.
Acta Neuropathologica Communications,
Journal Year:
2023,
Volume and Issue:
11(1)
Published: March 13, 2023
Abstract
In
the
contexts
of
aging,
injury,
or
neuroinflammation,
activated
microglia
signaling
with
TNF-α,
IL-1α,
and
C1q
induces
a
neurotoxic
astrocytic
phenotype,
classified
as
A1,
A1-like,
neuroinflammatory
reactive
astrocytes.
contrast
to
typical
astrocytes,
which
promote
neuronal
survival,
support
synapses,
maintain
blood–brain
barrier
integrity,
these
astrocytes
downregulate
supportive
functions
begin
secrete
factors,
complement
components
like
C3,
chemokines
CXCL10,
may
facilitate
recruitment
immune
cells
across
BBB
into
CNS.
The
proportion
pro-inflammatory
increases
age
through
associated
activation,
are
particularly
abundant
in
neurodegenerative
disorders.
As
identification
astrocyte
phenotypes
progress,
their
molecular
cellular
effects
characterized
growing
array
neuropathologies.
Science,
Journal Year:
2023,
Volume and Issue:
380(6640)
Published: April 6, 2023
Contemporary
studies
have
completely
changed
the
view
of
brain
immunity
from
envisioning
as
isolated
and
inaccessible
to
peripheral
immune
cells
an
organ
in
close
physical
functional
communication
with
system
for
its
maintenance,
function,
repair.
Circulating
reside
special
niches
brain's
borders,
choroid
plexus,
meninges,
perivascular
spaces,
which
they
patrol
sense
a
remote
manner.
These
niches,
together
meningeal
lymphatic
skull
microchannels,
provide
multiple
routes
interaction
between
system,
addition
blood
vasculature.
In
this
Review,
we
describe
current
ideas
about
their
implications
aging,
diseases,
immune-based
therapeutic
approaches.
Signal Transduction and Targeted Therapy,
Journal Year:
2023,
Volume and Issue:
8(1)
Published: Oct. 13, 2023
Astroglia
are
a
broad
class
of
neural
parenchymal
cells
primarily
dedicated
to
homoeostasis
and
defence
the
central
nervous
system
(CNS).
contribute
pathophysiology
all
neurological
neuropsychiatric
disorders
in
ways
that
can
be
either
beneficial
or
detrimental
disorder
outcome.
Pathophysiological
changes
astroglia
primary
secondary
result
gain
loss
functions.
respond
external,
non-cell
autonomous
signals
associated
with
any
form
CNS
pathology
by
undergoing
complex
variable
their
structure,
molecular
expression,
function.
In
addition,
internally
driven,
cell
astroglial
innate
properties
lead
pathologies.
Astroglial
is
complex,
different
pathophysiological
states
phenotypes
context-specific
vary
disorder,
disorder-stage,
comorbidities,
age,
sex.
Here,
we
classify
into
(i)
reactive
astrogliosis,
(ii)
atrophy
function,
(iii)
degeneration
death,
(iv)
astrocytopathies
characterised
aberrant
forms
drive
disease.
We
review
across
spectrum
human
diseases
disorders,
including
neurotrauma,
stroke,
neuroinfection,
autoimmune
attack
epilepsy,
as
well
neurodevelopmental,
neurodegenerative,
metabolic
disorders.
Characterising
cellular
mechanisms
represents
new
frontier
identify
novel
therapeutic
strategies.
Nature Aging,
Journal Year:
2022,
Volume and Issue:
2(9), P. 837 - 850
Published: Sept. 20, 2022
Abstract
Microglia
and
complement
can
mediate
neurodegeneration
in
Alzheimer’s
disease
(AD).
By
integrative
multi-omics
analysis,
here
we
show
that
astrocytic
microglial
proteins
are
increased
Tau
P301S
synapse
fractions
with
age
a
C1q-dependent
manner.
In
addition
to
microglia,
identified
astrocytes
contribute
substantially
elimination
hippocampi.
Notably,
found
relatively
more
excitatory
marker
lysosomes,
whereas
lysosomes
contained
inhibitory
material.
C1q
deletion
reduced
astrocyte–synapse
association
decreased
synapses
engulfment
mice
rescued
density.
Finally,
an
AD
mouse
model
combines
β-amyloid
pathologies,
of
the
risk
gene
Trem2
impaired
phagocytosis
synapses,
engulfed
around
plaques.
Together,
our
data
reveal
contact
eliminate
manner
thereby
pathological
loss
compensate
for
dysfunction.
Nature Neuroscience,
Journal Year:
2023,
Volume and Issue:
26(3), P. 406 - 415
Published: Feb. 6, 2023
Alzheimer's
disease
(AD)
is
characterized
by
synaptic
loss,
which
can
result
from
dysfunctional
microglial
phagocytosis
and
complement
activation.
However,
what
signals
drive
aberrant
microglia-mediated
engulfment
of
synapses
in
AD
unclear.
Here
we
report
that
secreted
phosphoprotein
1
(SPP1/osteopontin)
upregulated
predominantly
perivascular
macrophages
and,
to
a
lesser
extent,
fibroblasts.
Perivascular
SPP1
required
for
microglia
engulf
upregulate
phagocytic
markers
including
C1qa,
Grn
Ctsb
presence
amyloid-β
oligomers.
Absence
Spp1
expression
mouse
models
results
prevention
loss.
Furthermore,
single-cell
RNA
sequencing
putative
cell-cell
interaction
analyses
reveal
induces
states
the
hippocampus
model
AD.
Altogether,
suggest
functional
role
cells-to-microglia
crosstalk,
whereby
modulates
