Frontiers in Pharmacology,
Год журнала:
2025,
Номер
16
Опубликована: Март 12, 2025
Background
Alzheimer’s
disease
(AD),
a
complex
neurodegenerative
associated
with
ageing,
is
the
leading
cause
of
dementia.
Few
people
early
AD
are
eligible
for
novel
Food
and
Drug
Administration
(FDA)-approved
drug
treatments.
Accordingly,
new
tools
diagnosis
markers
required
to
predict
subtypes,
individual
stages,
most
suitable
personalized
treatment.
We
previously
demonstrated
that
regulation
microRNA
(miR)-124
crucial
proper
neuronal
function
microglia
reshaping
in
human
cell
models.
Objective
The
aim
this
study
was
develop
an
efficient
miR-124-3p-loaded
exosome
strategy
validate
its
therapeutic
potential
using
multi-compartment
microfluidic
device
neuron–glia
recapitulates
age-AD
pathological
features.
Methods
results
Using
cortical
from
mouse
pups,
separated
glial
mixed
cultures
maintained
2
days
vitro
(stressed
microglia),
we
tested
effects
SH-SY5Y-derived
exosomes
loaded
miR-124-3p
mimic
either
by
their
direct
transfection
Exo-Fect™
(ET124)
or
isolation
secretome
miR-124
transfected
cells
(CT124).
ET124
revealed
better
delivery
effciency
higher
potent
improving
stressed
status
than
CT124.
Tricultures
SH-SY5Y
neuroblastoma
(SH-
WT
)
were
established
presence
line
(HMC3)
immortalized
astrocytes
(IM-HA)
tricompartmentalized
devices.
Replacement
SH-
those
APP695
SWE
tricultures
addition
low
doses
hydrogen
peroxide
used
simulate
late-onset
AD.
system
mimicked
AD-associated
neurodegeneration
neuroinflammation
processes.
Notably,
exhibited
neuroprotective
properties
across
three
types
model
preventing
apoptosis
neurite
deficits,
redirecting
microglial
profiles
towards
steady
state,
attenuating
inflammatory
miRNA
fingerprints
astrocyte
reactivity.
Conclusion
To
best
our
knowledge,
first
supporting
neuro-
immunoprotective
miR-124-engineered
triculture
platform,
recapitulating
age-related
susceptibility
Our
offers
medicines
patient
subtypes.
Signal Transduction and Targeted Therapy,
Год журнала:
2025,
Номер
10(1)
Опубликована: Март 7, 2025
Redox
signaling
acts
as
a
critical
mediator
in
the
dynamic
interactions
between
organisms
and
their
external
environment,
profoundly
influencing
both
onset
progression
of
various
diseases.
Under
physiological
conditions,
oxidative
free
radicals
generated
by
mitochondrial
respiratory
chain,
endoplasmic
reticulum,
NADPH
oxidases
can
be
effectively
neutralized
NRF2-mediated
antioxidant
responses.
These
responses
elevate
synthesis
superoxide
dismutase
(SOD),
catalase,
well
key
molecules
like
nicotinamide
adenine
dinucleotide
phosphate
(NADPH)
glutathione
(GSH),
thereby
maintaining
cellular
redox
homeostasis.
Disruption
this
finely
tuned
equilibrium
is
closely
linked
to
pathogenesis
wide
range
Recent
advances
have
broadened
our
understanding
molecular
mechanisms
underpinning
dysregulation,
highlighting
pivotal
roles
genomic
instability,
epigenetic
modifications,
protein
degradation,
metabolic
reprogramming.
findings
provide
foundation
for
exploring
regulation
mechanistic
basis
improving
therapeutic
strategies.
While
antioxidant-based
therapies
shown
early
promise
conditions
where
stress
plays
primary
pathological
role,
efficacy
diseases
characterized
complex,
multifactorial
etiologies
remains
controversial.
A
deeper,
context-specific
signaling,
particularly
redox-sensitive
proteins,
designing
targeted
aimed
at
re-establishing
balance.
Emerging
small
molecule
inhibitors
that
target
specific
cysteine
residues
proteins
demonstrated
promising
preclinical
outcomes,
setting
stage
forthcoming
clinical
trials.
In
review,
we
summarize
current
intricate
relationship
disease
also
discuss
how
these
insights
leveraged
optimize
strategies
practice.
Molecular Neurodegeneration,
Год журнала:
2025,
Номер
20(1)
Опубликована: Янв. 27, 2025
Alzheimer's
disease
(AD)
is
among
the
most
devastating
neurodegenerative
disorders
with
limited
treatment
options.
Emerging
evidence
points
to
involvement
of
lipid
dysregulation
in
development
AD.
Nevertheless,
precise
lipidomic
landscape
and
mechanistic
roles
lipids
pathology
remain
poorly
understood.
This
review
aims
highlight
significance
lipidomics
lipid-targeting
approaches
diagnosis
We
summarized
connection
between
human
brain
AD
at
both
genetic
species
levels.
briefly
introduced
technologies
discussed
potential
challenges
areas
future
advancements
field
for
research.
To
elucidate
central
role
converging
multiple
pathological
aspects
AD,
we
reviewed
current
knowledge
on
interplay
major
features,
including
amyloid
beta,
tau,
neuroinflammation.
Finally,
assessed
progresses
obstacles
lipid-based
therapeutics
proposed
strategies
leveraging
Journal of Neuroinflammation,
Год журнала:
2025,
Номер
22(1)
Опубликована: Янв. 13, 2025
Lipid
droplets
(LDs),
serving
as
the
convergence
point
of
energy
metabolism
and
multiple
signaling
pathways,
have
garnered
increasing
attention
in
recent
years.
Different
cell
types
within
central
nervous
system
(CNS)
can
regulate
to
generate
or
degrade
LDs
response
diverse
pathological
stimuli.
This
article
provides
a
comprehensive
review
on
composition
CNS,
their
generation
degradation
processes,
interaction
mechanisms
with
mitochondria,
distribution
among
different
types,
roles
played
by
these
cells-particularly
microglia
astrocytes-in
various
prevalent
neurological
disorders.
Additionally,
we
also
emphasize
paradoxical
role
post-cerebral
ischemia
inflammation
explore
potential
underlying
mechanisms,
aiming
identify
novel
therapeutic
targets
for
this
disease.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Июль 3, 2024
Abstract
Lipid
changes
in
the
brain
have
been
implicated
many
neurodegenerative
diseases
including
Alzheimer’s
Disease
(AD),
Parkinson’s
disease
and
Amyotrophic
Lateral
Sclerosis.
To
facilitate
comparative
lipidomic
research
across
brain-diseases
we
established
a
data
commons
named
Neurolipid
Atlas,
that
pre-populated
with
novel
human,
mouse
isogenic
induced
pluripotent
stem
cell
(iPSC)-derived
lipidomics
for
different
diseases.
We
show
iPSC-derived
neurons,
microglia
astrocytes
display
distinct
lipid
profiles
recapitulate
vivo
lipotypes.
Leveraging
multiple
datasets,
AD
risk
gene
ApoE4
drives
cholesterol
ester
(CE)
accumulation
human
recapitulating
CE
measured
brain.
Multi-omic
interrogation
of
revealed
plays
major
role
astrocyte
interferon-dependent
pathways
such
as
immunoproteasome
histocompatibility
complex
(MHC)
class
I
antigen
presentation.
through
enhanced
esterification
suppresses
immune
activation
astrocytes.
Our
commons,
available
at
neurolipidatlas.com,
provides
user-friendly
tool
knowledge
base
better
understanding
dyshomeostasis
Lipid
droplets
(LDs)
are
dynamic
cytoplasmic
lipid-storing
organelles
that
play
a
pivotal
role
in
maintaining
cellular
energy
balance,
lipid
homeostasis,
and
metabolic
signaling.
Dysregulation
of
metabolism,
particularly
excessive
lipogenesis,
contributes
to
the
abnormal
accumulation
LDs
nervous
system,
which
is
associated
with
several
neurodegenerative
diseases.
Circular
RNAs
(circRNAs)
new
class
non-coding
regulatory
widely
expressed
eukaryotes.
However,
only
subset
has
been
functionally
characterized.
Here,
we
identified
characterized
circular
RNA
circbabo(5,6,7,8S)
regulates
lipogenesis
neuronal
integrity
Drosophila
melanogaster.
derived
from
babo
locus
encodes
type
I
receptor
for
transforming
growth
factor
β
(TGF-β).
Depletion
flies
causes
elevated
droplet
accumulation,
progressive
photoreceptor
cell
loss
shortened
lifespan,
phenotypes
rescued
by
restoring
expression.
In
addition,
RNA-seq
epistasis
analyses
reveal
these
abnormalities
caused
aberrant
activation
SREBP
signaling
pathway.
Furthermore,
circbabo(5,6,7,8S)-depleted
tissues
display
enhanced
TGF-β
pathway
compromised
mitochondrial
function,
resulting
upregulation
reactive
oxygen
species
(ROS).
Moreover,
provide
evidence
protein
circbabo(5,6,7,8S)-p,
inhibits
interfering
assembly
babo/put
heterodimer
complex.
Lastly,
show
dysregulation
ROS/JNK/SREBP
cascade
responsible
LD
neurodegeneration,
lifespan
elicited
depletion.
Our
study
demonstrates
physiological
protein-coding
circRNA
regulating
metabolism
integrity.
Abstract
Genetics
and
other
data
modalities
indicate
that
microglia
play
a
critical
role
in
Alzheimer's
disease
progression,
but
details
of
the
disease-driving
influence
are
poorly
understood.
Microglial
cells
can
be
parsed
into
subtypes
based
on
their
histological
appearance.
One
subtype
microglia,
termed
dystrophic
is
characterized
structurally
by
fragmented
processes
cytoplasmic
decay,
presence
has
been
associated
with
ageing
neurodegeneration.
Recent
studies
suggest
interaction
between
tau
proteins
amyloid-β
might
induce
changes
potentially
linking
pathologies
to
effects
these
microglia.
We
developed
study
human
brains
test
hypothesis
involved
progression.
speculated
if
unique
neuropathological
change,
they
would
substantially
more
common
change
than
neurodegenerative
diseases
proteinopathies,
e.g.
α-synuclein
or
transactive
response
(TAR)
DNA-binding
protein
43
kDa
(TDP-43)
pathology.
Our
analyses
used
histologically
stained
sections
from
five
brain
regions
64
individuals
across
six
states,
healthy
controls
advanced
stages,
including
comparative
conditions
such
as
Lewy
body
limbic-predominant
age-related
TDP-43
encephalopathy
change.
Using
stereological
sampling
digital
pathology,
we
assessed
populations
ramified,
hypertrophic
found
significant
increase
areas
affected
early
suggesting
disease-specific
neuropathology.
Mediation
analysis
structural
equation
modelling
impact
regional
spread
In
mediation
model,
was
initiating
factor
leading
development
which
then
tau.
These
results
loss
protective
could
contribute
further
research
preserving
microglial
function
warranted.
