Journal of Clinical Investigation,
Год журнала:
2023,
Номер
133(14)
Опубликована: Июнь 6, 2023
Alzheimer's
disease
(AD)
is
the
most
common
cause
of
dementia.
The
APOE-ε4
allele
apolipoprotein
E
(APOE)
gene
strongest
genetic
risk
factor
for
late-onset
AD.
APOE
genotype
modulates
effect
sleep
disruption
on
AD
risk,
suggesting
a
possible
link
between
apoE
and
in
pathogenesis,
which
relatively
unexplored.
We
hypothesized
that
modifies
Aβ
deposition
plaque-associated
tau
seeding
spreading
form
neuritic
plaque-tau
(NP-tau)
pathology
response
to
chronic
deprivation
(SD)
an
isoform-dependent
fashion.
To
test
this
hypothesis,
we
used
APPPS1
mice
expressing
human
APOE-ε3
or
-ε4
with
without
AD-tau
injection.
found
SD
significantly
increased
peri-plaque
NP-tau
presence
APOE4
but
not
APOE3.
decreased
microglial
clustering
around
plaques
aquaporin-4
(AQP4)
polarization
blood
vessels
also
sleep-deprived
APPPS1:E4
injected
had
altered
behaviors
compared
APPPS1:E3
mice.
These
findings
suggest
critical
modifier
development
SD.
Signal Transduction and Targeted Therapy,
Год журнала:
2024,
Номер
9(1)
Опубликована: Фев. 16, 2024
Abstract
The
human
gastrointestinal
tract
is
populated
with
a
diverse
microbial
community.
vast
genetic
and
metabolic
potential
of
the
gut
microbiome
underpins
its
ubiquity
in
nearly
every
aspect
biology,
including
health
maintenance,
development,
aging,
disease.
advent
new
sequencing
technologies
culture-independent
methods
has
allowed
researchers
to
move
beyond
correlative
studies
toward
mechanistic
explorations
shed
light
on
microbiome–host
interactions.
Evidence
unveiled
bidirectional
communication
between
central
nervous
system,
referred
as
“microbiota–gut–brain
axis”.
microbiota–gut–brain
axis
represents
an
important
regulator
glial
functions,
making
it
actionable
target
ameliorate
development
progression
neurodegenerative
diseases.
In
this
review,
we
discuss
mechanisms
As
provides
essential
cues
microglia,
astrocytes,
oligodendrocytes,
examine
communications
microbiota
these
cells
during
healthy
states
Subsequently,
diseases
using
metabolite-centric
approach,
while
also
examining
role
microbiota-related
neurotransmitters
hormones.
Next,
targeting
intestinal
barrier,
blood–brain
meninges,
peripheral
immune
system
counteract
dysfunction
neurodegeneration.
Finally,
conclude
by
assessing
pre-clinical
clinical
evidence
probiotics,
prebiotics,
fecal
transplantation
A
thorough
comprehension
will
foster
effective
therapeutic
interventions
for
management
Cell,
Год журнала:
2023,
Номер
186(20), С. 4386 - 4403.e29
Опубликована: Сен. 1, 2023
Altered
microglial
states
affect
neuroinflammation,
neurodegeneration,
and
disease
but
remain
poorly
understood.
Here,
we
report
194,000
single-nucleus
transcriptomes
epigenomes
across
443
human
subjects
diverse
Alzheimer's
(AD)
pathological
phenotypes.
We
annotate
12
transcriptional
states,
including
AD-dysregulated
homeostatic,
inflammatory,
lipid-processing
states.
identify
1,542
AD-differentially-expressed
genes,
both
microglia-state-specific
disease-stage-specific
alterations.
By
integrating
epigenomic,
transcriptomic,
motif
information,
infer
upstream
regulators
of
cell
gene-regulatory
networks,
enhancer-gene
links,
transcription-factor-driven
state
transitions.
demonstrate
that
ectopic
expression
our
predicted
homeostatic-state
activators
induces
homeostatic
features
in
iPSC-derived
microglia-like
cells,
while
inhibiting
inflammation
can
block
inflammatory
progression.
Lastly,
pinpoint
the
AD-risk
genes
differential
their
during
AD
Overall,
provide
insights
underlying
state-specific
AD-stage-specific
alterations
at
unprecedented
resolution.
Nature,
Год журнала:
2024,
Номер
628(8006), С. 154 - 161
Опубликована: Март 13, 2024
Abstract
Several
genetic
risk
factors
for
Alzheimer’s
disease
implicate
genes
involved
in
lipid
metabolism
and
many
of
these
are
highly
expressed
glial
cells
1
.
However,
the
relationship
between
glia
pathology
remains
poorly
understood.
Through
single-nucleus
RNA
sequencing
brain
tissue
disease,
we
have
identified
a
microglial
state
defined
by
expression
droplet-associated
enzyme
ACSL1
with
ACSL1-positive
microglia
being
most
abundant
patients
having
APOE4/4
genotype.
In
human
induced
pluripotent
stem
cell-derived
microglia,
fibrillar
Aβ
induces
expression,
triglyceride
synthesis
droplet
accumulation
an
APOE-dependent
manner.
Additionally,
conditioned
media
from
droplet-containing
lead
to
Tau
phosphorylation
neurotoxicity
Our
findings
suggest
link
neurotoxic
microglia-derived
factors,
potentially
providing
therapeutic
strategies
disease.
Cell Reports,
Год журнала:
2023,
Номер
42(3), С. 112196 - 112196
Опубликована: Март 1, 2023
The
E4
allele
of
Apolipoprotein
E
(APOE)
is
associated
with
both
metabolic
dysfunction
and
a
heightened
pro-inflammatory
response:
two
findings
that
may
be
intrinsically
linked
through
the
concept
immunometabolism.
Here,
we
combined
bulk,
single-cell,
spatial
transcriptomics
cell-specific
spatially
resolved
analyses
in
mice
expressing
human
APOE
to
systematically
address
role
across
age,
neuroinflammation,
AD
pathology.
RNA
sequencing
(RNA-seq)
highlighted
immunometabolic
changes
APOE4
glial
transcriptome,
specifically
subsets
metabolically
distinct
microglia
enriched
brain
during
aging
or
following
an
inflammatory
challenge.
display
increased
Hif1α
expression
disrupted
tricarboxylic
acid
(TCA)
cycle
are
inherently
pro-glycolytic,
while
mass
spectrometry
imaging
highlight
E4-specific
response
amyloid
characterized
by
widespread
alterations
lipid
metabolism.
Taken
together,
our
emphasize
central
for
regulating
microglial
immunometabolism
provide
valuable,
interactive
resources
discovery
validation
research.
Signal Transduction and Targeted Therapy,
Год журнала:
2024,
Номер
9(1)
Опубликована: Апрель 26, 2024
The
induced
pluripotent
stem
cell
(iPSC)
technology
has
transformed
in
vitro
research
and
holds
great
promise
to
advance
regenerative
medicine.
iPSCs
have
the
capacity
for
an
almost
unlimited
expansion,
are
amenable
genetic
engineering,
can
be
differentiated
into
most
somatic
types.
been
widely
applied
model
human
development
diseases,
perform
drug
screening,
develop
therapies.
In
this
review,
we
outline
key
developments
iPSC
field
highlight
immense
versatility
of
modeling
therapeutic
applications.
We
begin
by
discussing
pivotal
discoveries
that
revealed
potential
a
nucleus
reprogramming
led
successful
generation
iPSCs.
consider
molecular
mechanisms
dynamics
as
well
numerous
methods
available
induce
pluripotency.
Subsequently,
discuss
various
iPSC-based
cellular
models,
from
mono-cultures
single
type
complex
three-dimensional
organoids,
how
these
models
elucidate
diseases.
use
examples
neurological
disorders,
coronavirus
disease
2019
(COVID-19),
cancer
diversity
disease-specific
phenotypes
modeled
using
iPSC-derived
cells.
also
used
high-throughput
screening
toxicity
studies.
Finally,
process
developing
autologous
allogeneic
therapies
their
alleviate
Trends in Endocrinology and Metabolism,
Год журнала:
2023,
Номер
34(8), С. 430 - 445
Опубликована: Июнь 24, 2023
Dysregulation
of
lipid
metabolism
has
emerged
as
a
central
component
many
neurodegenerative
diseases.
Variants
the
transport
protein,
apolipoprotein
E
(APOE),
modulate
risk
and
resilience
in
several
diseases
including
late-onset
Alzheimer's
disease
(LOAD).
Allelic
variants
gene,
APOE,
alter
cells
tissues
have
been
broadly
associated
with
other
cellular
systemic
phenotypes.
Targeting
APOE-associated
metabolic
pathways
may
offer
opportunities
to
disease-related
phenotypes
consequently,
attenuate
impart
multiple
We
review
molecular,
cellular,
tissue-level
alterations
that
arise
from
different
APOE
isoforms.
These
changes
could
help
elucidate
mechanisms
tune
resilience.
Cell stem cell,
Год журнала:
2023,
Номер
30(2), С. 120 - 136
Опубликована: Фев. 1, 2023
Adult
hippocampal
neurogenesis
(AHN)
drops
sharply
during
early
stages
of
Alzheimer's
disease
(AD),
via
unknown
mechanisms,
and
correlates
with
cognitive
status
in
AD
patients.
Understanding
AHN
regulation
could
provide
a
framework
for
innovative
pharmacological
interventions.
We
here
combine
molecular,
behavioral,
clinical
data
critically
discuss
the
multicellular
complexity
niche
relation
to
pathophysiology.
further
present
roadmap
toward
better
understanding
role
by
probing
promises
caveats
latest
technological
advancements
field
addressing
conceptual
methodological
challenges
ahead.
