Frontiers in Molecular Neuroscience,
Год журнала:
2024,
Номер
17
Опубликована: Янв. 21, 2024
Aging-related
memory
impairment
and
pathological
disorders
such
as
Alzheimer’s
disease
differ
between
males
females,
yet
little
is
known
about
how
aging-related
changes
in
the
transcriptome
chromatin
environment
sexes
hippocampus.
To
investigate
this
question,
we
compared
accessibility
landscape
gene
expression/alternative
splicing
pattern
of
young
adult
aged
mouse
hippocampus
both
females
using
ATAC-seq
RNA-seq.
We
detected
significant
aging-dependent
expression
genes
involved
immune
response
synaptic
function
alternative
myelin
sheath
genes.
found
sex-bias
hundreds
genes,
including
female-biased
male-biased
function.
Aging
was
associated
with
increased
male
female
hippocampus,
especially
repetitive
elements,
an
increase
LINE-1
transcription.
autosomes
X
chromosome,
enriched
at
promoters
CpG-rich
regions.
Sex
differences
were
amplified
aging,
findings
that
may
shed
light
on
sex
loss.
Experimental & Molecular Medicine,
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 20, 2025
Abstract
Neuroinflammation,
a
significant
contributor
to
various
neurodegenerative
diseases,
is
strongly
associated
with
the
aging
process;
however,
date,
no
efficacious
treatments
for
neuroinflammation
have
been
developed.
In
aged
mouse
brains,
number
of
infiltrating
immune
cells
increases,
and
key
transcription
factor
increased
chemokine
levels
nuclear
kappa
B
(NF-κB).
Exosomes
are
potent
therapeutics
or
drug
delivery
vehicles
materials,
including
proteins
regulatory
genes,
target
cells.
present
study,
we
evaluated
therapeutic
efficacy
exosomes
loaded
nondegradable
form
IκB
(Exo-srIκB),
which
inhibits
translocation
NF-κB
suppress
age-related
neuroinflammation.
Single-cell
RNA
sequencing
revealed
that
these
anti-inflammatory
targeted
macrophages
microglia,
reducing
expression
inflammation-related
genes.
Treatment
Exo-srIκB
also
suppressed
interactions
between
macrophages/microglia
T
in
brain.
We
demonstrated
successfully
alleviates
by
primarily
targeting
activated
partially
modulating
functions
interferon-responsive
microglia
Thus,
our
findings
highlight
as
potential
agent
treating
Glia,
Год журнала:
2023,
Номер
71(5), С. 1247 - 1258
Опубликована: Янв. 10, 2023
Abstract
Disability
in
multiple
sclerosis
(MS)
is
driven
part
by
the
failure
of
remyelination
and
progressive
neurodegeneration.
Microglia,
specifically
triggering
receptor
expressed
on
myeloid
cells
2
(TREM2),
a
factor
highly
microglia,
have
been
shown
to
play
an
important
role
remyelination.
Here,
using
focal
demyelination
model
brain,
we
demonstrate
that
persistent
TREM2
knockout
mice,
lasting
more
than
6
weeks
after
lysolecithin
injection
resulting
substantial
We
also
find
mice
exhibit
altered
glial
response
following
demyelination.
microglia
defects
migration
phagocytosis
myelin
debris.
In
addition,
human
monocyte‐derived
macrophages
from
subjects
with
mutation
prevalent
disease
show
defect
debris
phagocytosis.
Together,
highlight
central
signaling
neuroprotection.
These
findings
provide
insights
into
how
chronic
might
lead
axonal
damage
could
help
identify
novel
neuroprotective
therapeutic
targets
for
MS.
Neuron,
Год журнала:
2023,
Номер
111(19), С. 2954 - 2968
Опубликована: Июнь 28, 2023
In
Alzheimer's
disease
(AD),
Aβ
deposits
form
slowly,
several
decades
before
further
pathological
events
trigger
neurodegeneration
and
dementia.
However,
a
substantial
proportion
of
affected
individuals
remains
non-demented
despite
AD
pathology,
raising
questions
about
the
underlying
factors
that
determine
transition
to
clinical
disease.
Here,
we
emphasize
critical
function
resilience
resistance
factors,
which
extend
beyond
concept
cognitive
reserve
include
glial,
immune,
vascular
system.
We
review
evidence
use
metaphor
"tipping
points"
illustrate
how
gradually
forming
neuropathology
in
preclinical
stage
can
dementia
once
adaptive
functions
system
are
lost
self-reinforcing
cascades
unleashed.
Thus,
propose
an
expanded
framework
for
pathomechanistic
research
focuses
on
tipping
points
non-neuronal
mechanisms,
may
represent
previously
untapped
therapeutic
targets
AD.
Science Translational Medicine,
Год журнала:
2025,
Номер
17(780)
Опубликована: Янв. 8, 2025
In
multiple
sclerosis
(MS),
microglia
and
macrophages
within
the
central
nervous
system
(CNS)
play
an
important
role
in
determining
balance
among
demyelination,
neurodegeneration,
myelin
repair.
Phagocytic
regenerative
functions
of
these
CNS
innate
immune
cells
support
remyelination,
whereas
chronic
maladaptive
inflammatory
activation
promotes
lesion
expansion
disability,
particularly
progressive
forms
MS.
No
currently
approved
drugs
convincingly
target
CNS,
contributing
to
lack
therapies
aimed
at
promoting
remyelination
slowing
disease
progression
for
individuals
with
Here,
we
found
that
protein
kinase
C
(PKC)–modulating
drug
bryostatin-1
(bryo-1),
a
CNS-penetrant
compound
established
human
safety
profile,
shifts
transcriptional
programs
CNS-associated
from
proinflammatory
phenotype
vitro
vivo.
Treatment
bryo-1
stimulated
scavenger
pathways,
phagocytosis,
secretion
factors
prevented
neuroinflammatory
reactive
astrocytes
while
also
neuroaxonal
health
oligodendrocyte
differentiation.
line
findings,
systemic
treatment
mice
augmented
after
focal
demyelinating
injury.
Our
results
demonstrate
potential
possibly
wider
class
PKC
modulators
as
myelin-regenerative
supportive
agents
MS
other
neurologic
diseases.
Frontiers in Immunology,
Год журнала:
2025,
Номер
15
Опубликована: Янв. 14, 2025
Introduction
Remyelination
of
demyelinated
axons
can
occur
as
an
endogenous
repair
mechanism
in
multiple
sclerosis
(MS),
but
its
efficacy
varies
between
both
MS
individuals
and
lesions.
The
molecular
cellular
mechanisms
that
drive
remyelination
remain
poorly
understood.
Here,
we
studied
the
relation
microglia
activation
activity
MS.
Methods
We
correlated
regenerative
(CD163
+
)
inflammatory
(iNOS
with
BCAS1
oligodendrocytes,
subdivided
into
early-stage
(<3
processes)
late-stage
(≥3
cells
brain
donors
high
or
low
remyelinating
potential
remyelinated
lesions
active
ramified/amoeboid
(non-foamy)
foamy
microglia.
A
cohort
categorized
efficiently
(ERDs;
n=25)
(PRDs;
n=17)
was
included,
based
on
their
proportion
at
autopsy.
Results
discussion
hypothesized
more
CD163
oligodendrocytes
non-foamy
from
ERDs
iNOS
fewer
PRDs.
For
microglia,
however,
no
differences
were
observed
donor
groups.
In
line
our
hypothesis,
found
INOS
significantly
increased
PRDs
compared
to
within
lesions,
detected
comparison
Although
for
did
find
vs
Interestingly,
a
positive
correlation
identified
presence
oligodendrocytes.
These
findings
suggest
impaired
maturation
encountering
may
underlie
deficits
unsuccessful
lesion
Cell Reports,
Год журнала:
2023,
Номер
42(12), С. 113574 - 113574
Опубликована: Дек. 1, 2023
Multiple
sclerosis
(MS)
is
an
inflammatory
disease
characterized
by
myelin
loss.
While
therapies
exist
to
slow
MS
progression,
no
treatment
currently
exists
for
remyelination.
Remyelination,
linked
reduced
disability
in
MS,
relies
on
microglia
and
monocyte-derived
macrophages
(MDMs).
This
study
aims
understand
the
role
of
during
remyelination
lineage
tracing
depleting
them.
Microglial
reveals
that
both
MDMs
initially
accumulate,
but
later
dominate
lesion.
Microglia
engulf
equal
amounts
inhibitory
debris,
after
microglial
depletion,
compensate
engulfing
more
debris.
depletion
does,
however,
reduce
recruitment
proliferation
oligodendrocyte
progenitor
cells
(OPCs)
impairs
their
subsequent
differentiation
These
findings
underscore
essential
offer
insights
enhancing
this
process
understanding
regulation
