Translational Neurodegeneration,
Год журнала:
2024,
Номер
13(1)
Опубликована: Окт. 29, 2024
Abstract
Background
Persistent
innate
and
adaptive
immune
responses
in
the
brain
contribute
to
progression
of
Alzheimer’s
disease
(AD).
APOE4
,
most
important
genetic
risk
factor
for
sporadic
AD,
encodes
apolipoprotein
E4,
which
by
itself
is
a
potent
modulator
response.
However,
little
known
about
hub
that
governs
crosstalk
between
nervous
systems.
Transient
receptor
potential
vanilloid
type
1
(TRPV1)
channel
ligand-gated,
nonselective
cation
with
Ca
2+
permeability,
has
been
proposed
as
neuroprotective
target
AD.
Methods
Using
-sensitive
dyes,
dynamic
changes
microglia
were
measured,
including
exogenous
uptake
endoplasmic
reticulum
release.
The
mRFP-GFP-tagged
LC3
plasmid
was
expressed
characterize
role
TRPV1
autophagic
flux.
Transcriptomic
analyses
flow
cytometry
performed
investigate
effects
on
T
cells
from
APOE
-targeted
replacement
mice
microglia-specific
gene
deficiency.
Results
Both
derived
induced
pluripotent
stem
AD
patients
-related
tauopathy
mouse
model
showed
significantly
increased
cholesterol
biosynthesis
accumulation
compared
their
APOE3
counterparts.
Further,
dysregulation
associated
persistent
activation
elevation
major
histocompatibility
complex
II-dependent
antigen
presentation
microglia,
subsequently
accompanied
cell
infiltration.
In
addition,
TRPV1-mediated
transient
influx
mitigated
suppressing
transcriptional
sterol
regulatory
element-binding
protein
2,
promoted
activity
reduced
lysosomal
accumulation,
sufficient
resolve
excessive
response
neurodegeneration
model.
Moreover,
deficiency
accelerated
glial
inflammation,
an
Conclusions
findings
provide
new
perspectives
treatment
-dependent
Signal Transduction and Targeted Therapy,
Год журнала:
2024,
Номер
9(1)
Опубликована: Авг. 23, 2024
Abstract
Alzheimer’s
disease
(AD)
stands
as
the
predominant
form
of
dementia,
presenting
significant
and
escalating
global
challenges.
Its
etiology
is
intricate
diverse,
stemming
from
a
combination
factors
such
aging,
genetics,
environment.
Our
current
understanding
AD
pathologies
involves
various
hypotheses,
cholinergic,
amyloid,
tau
protein,
inflammatory,
oxidative
stress,
metal
ion,
glutamate
excitotoxicity,
microbiota-gut-brain
axis,
abnormal
autophagy.
Nonetheless,
unraveling
interplay
among
these
pathological
aspects
pinpointing
primary
initiators
require
further
elucidation
validation.
In
past
decades,
most
clinical
drugs
have
been
discontinued
due
to
limited
effectiveness
or
adverse
effects.
Presently,
available
primarily
offer
symptomatic
relief
often
accompanied
by
undesirable
side
However,
recent
approvals
aducanumab
(
1
)
lecanemab
2
Food
Drug
Administration
(FDA)
present
potential
in
disrease-modifying
Nevertheless,
long-term
efficacy
safety
need
Consequently,
quest
for
safer
more
effective
persists
formidable
pressing
task.
This
review
discusses
pathogenesis,
advances
diagnostic
biomarkers,
latest
updates
trials,
emerging
technologies
drug
development.
We
highlight
progress
discovery
selective
inhibitors,
dual-target
allosteric
modulators,
covalent
proteolysis-targeting
chimeras
(PROTACs),
protein-protein
interaction
(PPI)
modulators.
goal
provide
insights
into
prospective
development
application
novel
drugs.
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
Nature Neuroscience,
Год журнала:
2023,
Номер
26(12), С. 2131 - 2146
Опубликована: Ноя. 9, 2023
Social
behaviors
are
innate
and
supported
by
dedicated
neural
circuits,
but
the
molecular
identities
of
these
circuits
how
they
established
developmentally
shaped
experience
remain
unclear.
Here
we
show
that
medial
amygdala
(MeA)
cells
originating
from
two
embryonically
parcellated
developmental
lineages
have
distinct
response
patterns
functions
in
social
behavior
male
mice.
MeA
expressing
transcription
factor
Foxp2
(MeA
International Journal of Molecular Sciences,
Год журнала:
2024,
Номер
25(13), С. 6901 - 6901
Опубликована: Июнь 24, 2024
Alzheimer's
disease
(AD)
is
the
most
prevalent
neurodegenerative
disorder
and
affects
millions
of
individuals
globally.
AD
associated
with
cognitive
decline
memory
loss
that
worsens
aging.
A
statistical
report
using
U.S.
data
on
estimates
approximately
6.9
million
suffer
from
AD,
a
number
projected
to
surge
13.8
by
2060.
Thus,
there
critical
imperative
pinpoint
address
its
hallmark
tau
protein
aggregation
early
prevent
manage
debilitating
effects.
Amyloid-β
proteins
are
primarily
formation
plaques
neurofibril
tangles
in
brain.
Current
research
efforts
focus
degrading
amyloid-β
or
inhibiting
their
synthesis,
particularly
targeting
APP
processing
hyperphosphorylation,
aiming
develop
effective
clinical
interventions.
However,
navigating
this
intricate
landscape
requires
ongoing
studies
trials
treatments
truly
make
difference.
Genome-wide
association
(GWASs)
across
various
cohorts
identified
40
loci
over
300
genes
AD.
Despite
wealth
genetic
data,
much
remains
be
understood
about
functions
these
role
process,
prompting
continued
investigation.
By
delving
deeper
into
associations,
novel
targets
such
as
kinases,
proteases,
cytokines,
degradation
pathways,
offer
new
directions
for
drug
discovery
therapeutic
intervention
This
review
delves
biological
pathways
disrupted
identifies
how
variations
within
could
serve
potential
treatment
strategies.
Through
comprehensive
understanding
molecular
underpinnings
researchers
aim
pave
way
more
therapies
can
alleviate
burden
devastating
disease.
Alzheimer s & Dementia,
Год журнала:
2024,
Номер
20(9), С. 6590 - 6605
Опубликована: Июль 19, 2024
Abstract
INTRODUCTION
The
apolipoprotein
E
gene
(
APOE
)
is
an
established
central
player
in
the
pathogenesis
of
Alzheimer's
disease
(AD),
with
distinct
apoE
isoforms
exerting
diverse
effects.
influences
not
only
amyloid‐beta
and
tau
pathologies
but
also
lipid
energy
metabolism,
neuroinflammation,
cerebral
vascular
health,
sex‐dependent
manifestations.
Furthermore,
ancestral
background
may
significantly
impact
link
between
AD,
underscoring
need
for
more
inclusive
research.
METHODS
In
2023,
Association
convened
multidisciplinary
researchers
at
“AAIC
Advancements:
APOE”
conference
to
discuss
various
topics,
including
their
roles
AD
pathogenesis,
progress
apoE‐targeted
therapeutic
strategies,
updates
on
models
interventions
that
modulate
expression
function.
RESULTS
This
manuscript
presents
highlights
from
provides
overview
opportunities
further
research
field.
DISCUSSION
Understanding
apoE's
multifaceted
will
help
develop
targeted
advance
field
precision
medicine.
Highlights
a
disease.
exerts
numerous
effects
throughout
brain
amyloid‐beta,
tau,
other
pathways.
AAIC
encouraged
discussions
collaborations
understanding
role
APOE.
Science Translational Medicine,
Год журнала:
2025,
Номер
17(781)
Опубликована: Янв. 15, 2025
Alzheimer’s
disease
(AD)
is
the
most
prevalent
neurodegenerative
disorder.
Antiamyloid
antibody
treatments
modestly
slow
progression
in
mild
dementia
due
to
AD.
Emerging
evidence
shows
that
homeostatic
dysregulation
of
brain
immune
system,
especially
orchestrated
by
microglia,
plays
an
important
role
onset
and
progression.
Thus,
a
major
question
how
modulate
phenotype
function
microglia
treat
Xenon
(Xe)
gas
noble
used
human
patients
as
anesthetic
neuroprotectant
for
treating
injuries.
Xe
penetrates
blood-brain
barrier,
which
could
make
it
effective
therapeutic.
To
assess
effect
on
AD
pathology,
we
designed
custom
inhalation
chamber
treated
several
mouse
models
with
gas.
treatment
induced
adopt
intermediate
activation
state
have
termed
pre–neurodegenerative
(pre-MGnD).
This
microglial
phenotypic
transition
was
observed
acute
neurodegeneration
amyloidosis
(APP/PS1
5xFAD
mice)
tauopathy
(P301S
mice).
enhanced
amyloid
plaque
compaction
reduced
dystrophic
neurites
APP/PS1
models.
Moreover,
atrophy
neuroinflammation
improved
nest-building
behavior
P301S
mice.
Mechanistically,
toward
pre-MGnD
through
IFN-γ
signaling
maintained
phagocytic
response
mice
while
suppressing
proinflammatory
These
results
support
translation
approach
Journal of Neurochemistry,
Год журнала:
2025,
Номер
169(3)
Опубликована: Март 1, 2025
ABSTRACT
Synaptic
homeostasis
of
the
principal
neurotransmitters
glutamate
and
GABA
is
tightly
regulated
by
an
intricate
metabolic
coupling
between
neurons
astrocytes
known
as
glutamate/GABA‐glutamine
cycle.
In
this
cycle,
take
up
from
synapse
convert
these
into
glutamine.
Astrocytic
glutamine
subsequently
transferred
to
neurons,
serving
precursor
for
neuronal
synthesis.
The
cycle
integrates
multiple
cellular
processes,
including
neurotransmitter
release,
uptake,
synthesis,
metabolism.
All
processes
are
deeply
interdependent
closely
coupled
energy
Astrocytes
display
highly
active
mitochondrial
oxidative
metabolism
several
unique
features,
glycogen
storage
pyruvate
carboxylation,
which
essential
sustain
continuous
release.
However,
new
roles
oligodendrocytes
microglia
in
recycling
emerging.
Malfunction
can
lead
severe
synaptic
disruptions
may
be
implicated
brain
diseases.
Here,
I
review
central
aspects
recent
advances
highlight
how
functionally
connected
critical
functions
First,
overview
glutamate,
GABA,
transport
provided
relation
recycling.
Then,
reviewed,
with
a
special
emphasis
on
glial
cells.
Finally,
discuss
aberrant
linked
neurodegeneration
disease,
focusing
astrocyte
dysfunction
lipid
emerging
pathological
mechanisms.
Instead
viewing
individual
biochemical
more
holistic
integrative
approach
needed
advance
our
understanding
modulates
function
both
health
disease.
image