Microglia measured by TSPO PET are associated with Alzheimer's disease pathology and mediate key steps in a disease progression model
Alzheimer s & Dementia,
Год журнала:
2024,
Номер
20(4), С. 2397 - 2407
Опубликована: Фев. 1, 2024
Abstract
INTRODUCTION
Evidence
suggests
microglial
activation
precedes
regional
tau
and
neurodegeneration
in
Alzheimer's
disease
(AD).
We
characterized
microglia
with
translocator
protein
(TSPO)
positron
emission
tomography
(PET)
within
an
AD
progression
model
where
global
amyloid
beta
(Aβ)
local
neurodegeneration,
resulting
cognitive
impairment.
METHODS
Florbetaben,
PBR28,
MK‐6240
PET,
T1
magnetic
resonance
imaging,
measures
were
performed
19
cognitively
unimpaired
older
adults
22
patients
mild
impairment
or
to
examine
associations
among
activation,
Aβ,
tau,
cognition,
adjusting
for
neurodegeneration.
Mediation
analyses
evaluated
the
possible
role
of
along
model.
RESULTS
Higher
PBR28
uptake
was
associated
higher
lower
MMSE
score,
independent
mediated
between
early
middle
Braak
stages,
cognition.
DISCUSSION
Microglia
are
pathology
cognition
may
mediate
relationships
subsequent
steps
progression.
Язык: Английский
Brain resident microglia in Alzheimer’s disease: foe or friends
Inflammopharmacology,
Год журнала:
2024,
Номер
32(5), С. 2781 - 2800
Опубликована: Авг. 21, 2024
Язык: Английский
Antagonizing Il10 and Il4 signaling via intracerebral decoy receptor expression attenuates Aβ accumulation
Acta Neuropathologica Communications,
Год журнала:
2025,
Номер
13(1)
Опубликована: Март 7, 2025
Abstract
Multiple
lines
of
evidence
indicate
that
immune
signaling
can
impact
the
pathological
progression
in
Alzheimer’s
disease
(AD),
including
amyloid
deposition,
tau
aggregation,
synaptic
pathology
and
neurodegenerative
trajectory.
In
earlier
studies,
we
reported
intracerebral
expression
anti-inflammatory
cytokines,
Interleukin-10
(Il10)
Interleukin-4
(Il4),
increased
β
(Aβ)
burden
TgCRND8
mice,
a
preclinical
model
AD-type
amyloidosis.
As
both
receptor
(IL10R)
(IL4R)
are
upregulated
an
age-progressive
manner
rodent
models
AD
specific
regions
human
brains,
hypothesized
decoy
strategy
specifically
targeting
Il10
Il4
could
have
disease-modifying
effect.
We
derivatized
ectodomains
mouse
Il10R
(sIl10R)
Il4R
(sIl4R)
into
corresponding
recombinant
solubilized
forms
delivered
these
intracranially
neonatal
mice
or
hippocampally
adult
with
pre-existing
Aβ
deposits.
AAV-mediated
sIl10R
sIl4R
robustly
attenuated
when
expressed
neonatally
while
hippocampus
injection
cohort,
AAV-sIl4R,
but
not
sIl10R,
reduced
burden.
had
opposing
effects
on
microglial
astrocyte
proliferation,
generally
reducing
gliosis.
RNAseq
analysis
showed
likely
acts
as
checkpoint
inhibitor
show
unexpected
impacts
genes
related
to
circadian
rhythm.
Notably,
neither
nor
altered
two
transgenic
models,
despite
robust
glial
proliferation.
Together,
data
reveal
mediated
physiological
beneficially
deposition
thus
represent
novel
immunomodulatory
approaches
for
therapy.
Язык: Английский
Excessive Alcohol Use as a Risk Factor for Alzheimer’s Disease: Epidemiological and Preclinical Evidence
Advances in experimental medicine and biology,
Год журнала:
2025,
Номер
unknown, С. 211 - 242
Опубликована: Янв. 1, 2025
Язык: Английский
Role of Achyranthes aspera in neurodegenerative diseases: current evidence and future directions
Frontiers in Pharmacology,
Год журнала:
2025,
Номер
16
Опубликована: Апрель 9, 2025
Neurodegenerative
diseases
are
caused
by
the
progressive
degeneration
of
neurons
and/or
their
myelin
sheaths,
ultimately
leading
to
cognitive
and
motor
dysfunction.
Due
complex
pathogenesis
limited
efficacy
therapeutic
drugs,
these
have
attracted
significant
attention.
Achyranthes
aspera,
belongs
family
Amaranthaceae,
has
been
extensively
used
in
traditional
folk
medicines
for
treatment
various
ailments.
Modern
research
revealed
that
aspera
possesses
pharmacological
effects,
including
cardiocerebrovascular
protection,
immune
regulation,
antioxidation,
anti-aging.
Furthermore,
neuroprotective
effects
confirmed
numerous
scientific
studies.
This
review
focuses
on
primary
mechanisms
prevention
neurodegenerative
diseases,
as
well
potential
application
prospects.
aims
provide
insights
into
clinical
applications
directions
diseases.
Язык: Английский
Neutrophil-to-Lymphocyte Ratio in the Alzheimer’s Disease Continuum
International Journal of Molecular Sciences,
Год журнала:
2025,
Номер
26(11), С. 5157 - 5157
Опубликована: Май 28, 2025
Alzheimer’s
disease
(AD)
is
a
neurodegenerative
disorder
defined
clinically
by
progressive
cognitive
decline
and
memory
impairment
pathologically
the
accumulation
of
amyloid-beta
plaques,
tau
neurofibrillary
tangles,
neuroinflammation,
immune
system
dysregulation.
Peripheral
biomarkers
are
gaining
attention
as
valuable
tools
for
elucidating
neuroinflammatory
mechanisms
in
AD
continuum,
with
potential
implications
diagnosis
prognosis.
Among
these,
neutrophil-to-lymphocyte
ratio
(NLR)
has
emerged
promising
systemic
inflammatory
marker.
NLR,
readily
available
cost-effective
parameter
derived
from
routine
blood
tests,
reflects
balance
between
innate
adaptive
responses.
Elevated
NLR
been
associated
mild
(MCI),
showing
correlations
severity,
amyloid
burden,
neuroinflammation.
Increased
neutrophil
counts
may
contribute
to
neurodegeneration
through
oxidative
stress
pro-inflammatory
cytokine
release,
while
decreased
lymphocyte
levels
suggest
impaired
immunity.
However,
despite
growing
evidence,
clinical
utility
remains
debated
due
heterogeneity
study
populations
confounding
factors,
such
comorbidities
medication
effects.
This
review
provides
comprehensive
analysis
association
throughout
continuum.
Future
research
should
prioritize
longitudinal
studies
integrative
approaches
that
combine
other
markers
enhance
early
personalized
therapeutic
strategies.
Язык: Английский
Microglial responses partially mediate the effect of Aβ on cognition in Alzheimer's disease
Alzheimer s & Dementia,
Год журнала:
2024,
Номер
20(11), С. 8028 - 8037
Опубликована: Окт. 11, 2024
Abstract
INTRODUCTION
Microglial
responses
are
an
integral
part
of
Alzheimer's
disease
(AD)
pathology
and
associated
with
amyloid
beta
(Aβ)
deposition.
This
study
aimed
to
investigate
the
effects
Aβ
microglial
on
global
cognitive
impairment.
METHODS
In
this
longitudinal
study,
28
patients
mild
impairment
11
healthy
controls
underwent
C‐PK11195
C‐Pittsburgh
compound
B
positron
emission
tomography
(PET),
structural
magnetic
resonance
imaging
scans,
ratings
at
baseline
2‐year
follow‐up.
Correlations
between
PET
uptake
cognition
were
assessed.
Additionally,
mediation
effect
response
association
load
was
RESULTS
both
independently
detrimental
performance
baseline;
however,
follow‐up
partially
mediated
by
response.
DISCUSSION
As
AD
progresses,
mediates
aggregated
cognition.
Highlights
a
(Aβ),
responses,
performance.
affect
in
early
disease.
later
stages.
Язык: Английский
Hippocampal purinergic P2X7 receptor level is increased in Alzheimer’s disease patients, and associated with amyloid and tau pathologies
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Фев. 28, 2024
Abstract
INTRODUCTION
The
purinergic
receptor
P2X7R,
which
is
expressed
on
microglia
and
astrocytes,
plays
an
important
role
in
Alzheimer’s
disease
(AD).
We
aimed
to
characterize
the
alterations
P2X7R
expression
AD
patients
by
APOE
ε4
allele,
age
sex,
as
well
its
association
with
amyloid
tau
pathology.
METHODS
staining
quantitative
analysis
of
amyloid,
tau,
astrocytes
were
performed
postmortem
hippocampal
tissues
from
35
patients;
31
nondemented
controls;
caudate/putamen
tissue
corticobasal
degeneration
(CBD),
progressive
supranuclear
palsy
(PSP)
bran
aged
3×Tg
mouse
model
AD.
RESULTS
Activated
reactive
observed
hippocampi
exhibited
altered
morphology
denser
cells
pronounced
ramifications.
Hippocampal
intensity
was
greater
subfields
than
those
controls
correlated
level
Braak
stage
not
affected
APOEε4
or
age.
increased
around
Aβ
plaques,
cerebral
angiopathy,
inclusions
hippocampus
CBD
PSP
patients.
DISCUSSION
found
compared
non-demented
control,
pathologies.
a
potential
marker
for
neuroinflammation
Язык: Английский
Alzheimers-associated inflammatory alterations mediate tau-associated neurodegeneration in limbic and temporal regions across clinical variants of Alzheimers disease
medRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Ноя. 4, 2024
Abstract
Objectives
Microglia
monitor
and
respond
to
the
brain
’
s
microenvironment
maintain
homeostasis.
However,
in
Alzheimer
disease
related
dementias
(ADRD),
microglia
may
contribute
pathology.
We
hypothesized
that
AD-related
inflammatory
changes,
measured
with
TSPO
PET,
would
be
locally
associated
amyloid,
tau,
neurodegeneration,
influence
key
pathways
among
them.
Methods
Participants
(21
controls,
25
ADRD)
from
Longitudinal
Imaging
of
Microglial
Activation
Different
Clinical
Variants
Disease
study
underwent
baseline
amyloid
PET
(Florbetaben
SUVR),
tau
(MK6240
(ER176
structural
MRI
(gray
matter
volume).
Cognitive
assessments
consensus
diagnoses
(e.g.,
MCI,
AD,
PCA,
FTD,
LATE)
were
performed
at
CUIMC
ADRC
biomarker
information
when
available.
evaluated
regional
colocalization
elevation
ADRD
compared
associations
ATN
biomarkers,
mediations
along
pathways.
Sensitivity
analyses
stratified
by
positivity.
Results
Elevated
was
spatially
colocalized
elevated
(8
regions),
(7
neurodegeneration
(4
regions).
Higher
limbic,
temporal,
parietal
regions
higher
(0.8
2.3,
p<0.03),
which
remained
significant
after
adjusting
for
inferior
cortex.
mediated
association
between
limbic
temporal
(−0.27
-0.39,
p<0.02;
43%
89%
total
effect),
while
did
not
mediate
neurodegeneration.
also
as
well
across
progressive
Braak
stages,
but
only
amyloid-positive
ADRD.
Conclusion
Across
different
underlying
microenvironments
pathology/copathology)
are
sensitive,
density
greater
burden
tau-associated
Glia
represent
a
promising
target
intervention
strategies
ADRD-associated
Язык: Английский