Beyond Amyloid and Tau: The Critical Role of Microglia in Alzheimer’s Disease Therapeutics
Biomedicines,
Год журнала:
2025,
Номер
13(2), С. 279 - 279
Опубликована: Янв. 23, 2025
Alzheimer’s
disease
(AD)
is
traditionally
viewed
through
the
lens
of
amyloid
cascade
hypothesis,
implicating
amyloid-beta
and
tau
protein
aggregates
as
main
pathological
culprits.
However,
burgeoning
research
points
to
brain’s
resident
immune
cells,
microglia,
critical
players
in
AD
pathogenesis,
progression,
potential
therapeutic
interventions.
This
review
examines
dynamic
roles
microglia
within
intricate
framework
AD.
We
detail
involvement
these
cells
neuroinflammation,
explaining
how
their
activation
response
fluctuations
may
influence
trajectory.
further
elucidate
complex
relationship
between
pathology.
study
highlights
dual
nature
which
contribute
both
aggregation
clearance
protein.
Moreover,
an
in-depth
analysis
interplay
unveils
significant,
yet
often
overlooked,
impact
this
interaction
on
neurodegeneration
Shifting
from
conventional
approaches,
we
assess
current
treatments
primarily
targeting
introduce
novel
strategies
that
involve
manipulating
microglial
functions.
These
innovative
methods
herald
a
paradigm
shift
management
Finally,
explore
field
precision
diagnosis
pursuit
robust
biomarkers.
underline
more
profound
comprehension
biology
could
enrich
essential
areas,
potentially
paving
way
for
accurate
diagnostic
tools
tailored
treatment
strategies.
In
conclusion,
expands
perspective
pathology
treatment,
drawing
attention
multifaceted
microglia.
As
continue
enhance
our
understanding
microglial-focused
interventions
emerge
promising
frontier
bolster
arsenal
fight
against
Язык: Английский
Neuroinflammatory Biomarkers in Alzheimer’s Disease: From Pathophysiology to Clinical Implications
International Journal of Molecular Sciences,
Год журнала:
2024,
Номер
25(22), С. 11941 - 11941
Опубликована: Ноя. 6, 2024
The
identification
of
neuroinflammation
as
a
critical
factor
in
Alzheimer's
disease
(AD)
has
expanded
the
focus
research
beyond
amyloid-β
and
tau
pathology.
neuroinflammatory
fluid
biomarkers
GFAP,
sTREM2,
YKL-40
have
gained
attention
for
their
potential
early
detection
monitoring
progression.
Plasma
GFAP
demonstrated
promise
predicting
conversion
from
mild
cognitive
impairment
to
AD
dementia,
while
sTREM2
highlights
microglial
activation,
although
there
are
conflicting
results
regarding
its
dynamics
pathogenesis.
Advanced
imaging
techniques,
such
PET
tracers
targeting
TSPO
MAO-B,
also
been
developed
visualize
glial
activation
vivo,
offering
spatial
temporal
insights
into
processes.
However,
clinical
implementation
these
faces
challenges
due
lack
specificity,
many
them
can
be
elevated
other
conditions.
Therapeutic
strategies
emerging,
with
TREM2-targeting
therapies
antidiabetic
drugs
like
GLP-1
receptor
agonists
showing
modulating
activity.
Nevertheless,
complexity
neuroinflammation,
which
encompasses
both
protective
harmful
responses,
necessitates
further
fully
unravel
role
optimize
therapeutic
approaches
AD.
Язык: Английский
Unraveling the inflammation–degeneration tangle in early MS: preliminary insights from ferritin, neurogranin, TREM2, and retinal ganglion cell layer
Journal of Neurology,
Год журнала:
2025,
Номер
272(2)
Опубликована: Янв. 15, 2025
Multiple
sclerosis
(MS)
involves
a
complex
interplay
between
immune-mediated
inflammation
and
neurodegeneration.
Recent
advances
in
biomarker
research
have
provided
new
insights
into
the
molecular
underpinnings
of
MS,
including
ferritin,
neurogranin,
Triggering
Receptor
Expressed
on
Myeloid
cells
2
(TREM2),
neurofilaments
light
chain.
This
pilot
study
aims
to
investigate
levels
these
biomarkers
cerebrospinal
fluid
(CSF)
MS
patients
explore
their
associations
with
clinical,
cognitive,
optical
coherence
tomography
(OCT)
parameters.
cross-sectional
included
26
relapsing
(RMS)
13
symptomatic
controls
(SCs).
Clinical,
OCT
assessments
were
performed,
CSF
samples
analyzed
for
TREM2,
neurofilaments.
Neurogranin
significantly
higher
RMS
compared
SCs
(p
=
0.04),
receiver-operating
characteristic
(ROC)
analysis
indicated
that
neurogranin
could
be
considered
disease
(AUC
0.733,
p
0.01).
Ferritin
showed
strong
positive
correlation
(r
0.690,
<
0.01),
both
inversely
correlated
retinal
ganglion
cell
layer
(GCL)
thickness.
TREM2
was
positively
associated
baseline
Expanded
Disability
Status
Scale
score.
suggests
may
potential
at
time
diagnosis,
highlights
relationship
inflammation,
oxidative
stress,
neuronal
damage
MS.
The
inverse
association
ferritin
GCL
thickness
warrants
further
investigation
role
iron
metabolism
synaptic
early
stages
disease.
Язык: Английский
Acute TREM2 inhibition depletes MAFB-high microglia and hinders remyelination
Proceedings of the National Academy of Sciences,
Год журнала:
2025,
Номер
122(13)
Опубликована: Март 25, 2025
We
investigated
the
role
of
Triggering
Receptor
Expressed
on
Myeloid
cells
2
(TREM2)
in
myelin
regeneration
brain.
TREM2
is
a
receptor
that
activates
microglia,
which
are
crucial
for
clearing
debris
and
promoting
remyelination.
Previous
studies
mouse
model
demyelination
induced
by
copper-chelating
agent
Cuprizone
(CPZ)
have
shown
stimulation
with
monoclonal
antibody
reduces
demyelination,
while
deleting
Trem2
gene
mice
impairs
Here,
we
blocked
function
acutely
an
during
both
remyelination
phases
CPZ
analyzed
impact
treatment
myelination
expression
single
cells.
found
blocking
depleted
distinct
population
microglia
high
transcription
factor
MAFB
The
loss
these
MAFB-high
was
linked
to
impaired
generation
myelinating
oligodendrocytes.
Importantly,
identified
+
acute
acute-chronic
brain
lesions
from
individuals
multiple
sclerosis
(MS),
but
not
inactive
lesions.
conclude
essential
maintaining
associated
repair.
This
finding
has
significant
implications
understanding
demyelinating
diseases
like
MS
suggests
stimulating
could
be
promising
therapeutic
approach
Язык: Английский
The dual role of microglia in Alzheimer’s disease: from immune regulation to pathological progression
Frontiers in Aging Neuroscience,
Год журнала:
2025,
Номер
17
Опубликована: Март 27, 2025
Alzheimer’s
disease
(AD)
is
a
widespread
neurodegenerative
disorder
and
one
of
the
major
challenges
for
public
health.
Despite
extensive
research,
role
microglia
in
AD
remains
complex
dual.
The
aim
this
review
to
summarize
most
recent
advances
research
regarding
dual
concerning
both
immunomodulation
pathological
progression
by
considering
mechanisms
activation
microglia,
effects
on
Aβ
clearance,
tau
pathology,
impacts
due
genetic
variations
microglial
functions.
Among
these
findings
are
status
M1
M2
phenotypes,
crucial
that
variants
like
TREM2
have
modulating
response
microglia.
This
describes
how
modulation
signaling
pathway
might
be
exploited
therapeutically
treatment
underlines
relevance
personalized
medicine
approach.
Язык: Английский
Compound muscle action potential as an early functional in vivo measure of Sarm1 inhibition after sciatic nerve transection
Seong Kwon Hur,
Rebecca Leahey,
Mitchell Geringer
и другие.
Journal of Neuropathology & Experimental Neurology,
Год журнала:
2025,
Номер
unknown
Опубликована: Июнь 6, 2025
Abstract
The
NADase
sterile
alpha
and
TIR
motif
containing
1
(Sarm1)
protein
drives
axon
degeneration
after
injury.
Loss
or
inhibition
of
Sarm1
structurally
protects
axons
sciatic
nerve
transection
(SNT)
in
vivo
but
whether
also
functional
loss
injury
is
less
clear.
We
established
compound
muscle
action
potential
(CMAP)
as
a
novel
correlate
activation
SNT
mouse
model
evaluated
its
relationship
with
biochemical
Cellpose-based
histological
detection
measure.
CMAP
amplitudes
were
elicited
8
h
post-SNT
reached
near-floor
levels
by
24
h.
Decreases
amplitude
are
delayed
gene
dose-dependent
manner
knockout
mice
pharmacological
inhibition.
Myelinated
density,
the
NAD
hydrolysis
product
cyclic
adenosine
diphosphate
ribose
(cADPR),
plasma
biomarker
neurofilament
light
(NfL)
all
altered
Sarm1-dependent
manner.
In
wild
type
mice,
density
NfL
at
time
points
that
cADPR
loss,
indicating
deficits
preceded
structural
deficits.
conclude
declines
measures
can
serve
novel,
preclinical,
functional,
pharmacodynamic
readout
for
Язык: Английский
CD33 Ameliorates Surgery-Induced Spatial Learning and Memory Impairments Through TREM2
Molecular Neurobiology,
Год журнала:
2024,
Номер
unknown
Опубликована: Авг. 1, 2024
Язык: Английский
Identification of conserved and tissue-restricted transcriptional profiles for lipid associated macrophages (LAMs)
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Сен. 26, 2024
Abstract
Macrophages
are
essential
immune
cells
present
in
all
tissues,
and
vital
for
maintaining
tissue
homeostasis,
surveillance,
responses.
Considerable
efforts
have
identified
shared
tissue-specific
gene
programs
macrophages
across
organs
during
homeostasis.
This
information
has
dramatically
enhanced
our
understanding
of
tissue-restricted
macrophage
programming
function.
However,
few
studies
addressed
the
overlapping
responses
subsets
following
inflammatory
One
subset
that
been
observed
several
studies,
lipid-associated
(LAMs),
gained
interest
due
to
their
unique
role
lipid
metabolism
potential
as
a
therapeutic
target.
LAMs
associated
with
regulating
disease
outcomes
metabolically
related
disorders
including
atherosclerosis,
obesity,
nonalcoholic
fatty
liver
(NAFLD).
In
this
study,
we
utilized
single-cell
RNA
sequencing
(scRNAseq)
data
profile
multiple
tissues
sterile
conditions
mice
humans.
Integration
from
various
models
revealed
share
set
conserved
transcriptional
profiles,
Trem2
Lpl
,
but
also
key
sets
LAM
programs.
Importantly,
markers
were
highly
human
populations
emerge
chronic
settings.
Overall,
analysis
provides
detailed
landscape
offers
insights
into
roles
metabolic
diseases.
These
may
help
instruct
appropriate
targets
broad
or
interventions
modulate
disease.
Язык: Английский
The Challenges of Modulating Neuroinflammation in Alzheimer's Disease and Multiple Sclerosis with TREM2 Agonistic Antibodies
Journal of Neuroscience,
Год журнала:
2024,
Номер
44(50), С. e1869242024 - e1869242024
Опубликована: Дек. 11, 2024
Alzheimer's
disease
(AD)
and
multiple
sclerosis
(MS)
are
neurodegenerative
diseases
in
which
aberrant
inflammatory
processes
thought
to
contribute
progressive
disability.
Although
MS
is
characterized
by
demyelinated
lesions
AD
amyloid-β
plaques
neurofibrillary
tangles,
both
involve
the
activation
of
resident
macrophages
known
as
microglia.
Microglia
act
central
mediators
neuroinflammation
through
a
variety
mechanisms
including
release
immunomodulatory
cytokines
phagocytosis
toxic
debris,
such
damaged
myelin
(Sen
et
al.,
2022;
Zhang
2023).
Acute
can
protect
nervous
system;
however,
dysregulation
this
response
lead
chronic
damaging
effects.
Consequently,
microglia
have
emerged
promising
therapeutic
targets
for
these
diseases.
The
triggering
receptor
expressed
myeloid
cells
2
(TREM2)
transmembrane
protein
that
key
regulator
(Ulland
Colonna,
2018;
TREM2
recognizes
damage-associated
lipids
instructs
respond
pathological
insults
proliferating,
initiating
phagocytosis,
increasing
energy
metabolism
(Schlepckow
2023;
Previous
studies
using
animal
models
shown
required
transition
from
resting
surveillance
state
into
disease-associated
(DAM),
actively
engage
with
core
features
pathology.
In
models,
enables
DAM
form
protective
barriers
around
demyelination
used
study
MS,
influences
recruitment
sites,
clearance
remyelination
(Cignarella
2020).
Activated
eventually
cleaved,
attenuating
releasing
soluble
(sTREM2).
role
sTREM2
unclear.
It
was
initially
considered
passive
biomarker
pathology;
more
recent
overexpression
associated
beneficial
…
Correspondence
should
be
addressed
Juliette
R.
Houchois
at
juliette.houchois{at}medschool.ox.ac.uk.
Язык: Английский