Journal of Alzheimer s Disease,
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 29, 2025
Background
Alzheimer’s
disease
(AD)
is
a
progressive
neurodegenerative
disorder
that
predominantly
affects
elderly
individuals
across
the
globe.
While
genetic,
environmental,
and
lifestyle
factors
are
known
to
influence
onset
of
AD,
underlying
mechanisms
remain
unclear.
Objective
To
elucidate
intricate
interplay
between
metabolites
immune
cell
activation
in
ethology
determine
their
collective
impact
on
AD
risk.
Methods
We
conducted
comprehensive
analysis
genome-wide
association
studies
data
examine
relationships
metabolites,
phenotypes,
risk
AD.
Our
study
encompassed
examination
involving
731
distinct
types,
1400
large
cohort
comprising10,520
cases
with
401,661
controls.
employed
univariate
Mendelian
randomization
assess
bidirectional
cells,
as
well
cells
Subsequently,
multivariate
was
then
applied
evaluate
potential
mediating
role
relationship
Results
Specific
histidine/pyruvate
ratio
homoarginine,
were
positively
associated
mediated
by
cells.
Conversely,
4-hydroxycoumarin
glycolithocholate
sulfate
showed
protective
associations
against
Immune
markers,
CD64
monocytes
HLA
DR
CD14
+
CD16
−
linked
higher
risk,
while
CD33
dim
CD11b
myeloid
CD8
T
protective.
Conclusions
This
highlights
critical
pathogenesis
demonstrating
how
interaction
specific
influences
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
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.
The Journal of Experimental Medicine,
Год журнала:
2024,
Номер
221(4)
Опубликована: Март 1, 2024
Alzheimer’s
disease
(AD)
is
characterized
by
amyloid
plaques
and
neurofibrillary
tangles,
in
addition
to
neuroinflammation
changes
brain
lipid
metabolism.
25-Hydroxycholesterol
(25-HC),
a
known
modulator
of
both
inflammation
metabolism,
produced
cholesterol
25-hydroxylase
encoded
Ch25h
expressed
as
“disease-associated
microglia”
signature
gene.
However,
whether
influences
tau-mediated
neurodegeneration
unknown.
Here,
we
show
that
the
absence
resultant
reduction
25-HC,
there
strikingly
reduced
age-dependent
hippocampus
entorhinal/piriform
cortex
PS19
mice,
which
express
P301S
mutant
human
tau
transgene.
Transcriptomic
analyses
bulk
hippocampal
tissue
single
nuclei
revealed
deficiency
mice
strongly
suppressed
proinflammatory
signaling
microglia.
Our
results
suggest
key
role
for
Ch25h/25-HC
potentiating
promote
neurodegeneration.
may
represent
novel
therapeutic
target
primary
tauopathies,
AD,
other
neuroinflammatory
diseases.
Abstract
Neurodegenerative
diseases
(NDDs)
affect
more
than
50
million
people
worldwide,
posing
a
significant
global
health
challenge
as
well
high
socioeconomic
burden.
With
aging
constituting
one
of
the
main
risk
factors
for
some
NDDs
such
Alzheimer's
disease
(AD)
and
Parkinson's
(PD),
this
societal
toll
is
expected
to
rise
considering
predicted
increase
in
population
limited
progress
development
effective
therapeutics.
To
address
failure
rates
clinical
trials,
legislative
changes
permitting
use
alternatives
traditional
pre‐clinical
vivo
models
are
implemented.
In
regard,
microphysiological
systems
(MPS)
organ‐on‐a‐chip
(OoC)
platforms
constitute
promising
tool,
due
their
ability
mimic
complex
human‐specific
tissue
niches
vitro.
This
review
summarizes
current
modeling
using
OoC
technology
discusses
five
critical
aspects
still
insufficiently
addressed
date.
Taking
these
into
consideration
future
MPS
will
advance
vitro
translational
value
setting.
Nature Neuroscience,
Год журнала:
2024,
Номер
27(8), С. 1468 - 1474
Опубликована: Июнь 27, 2024
Abstract
Age-related
myelin
damage
induces
inflammatory
responses,
yet
its
involvement
in
Alzheimer’s
disease
remains
uncertain,
despite
age
being
a
major
risk
factor.
Using
mouse
model
of
disease,
we
found
that
amyloidosis
itself
triggers
age-related
oligodendrocyte
and
damage.
Mechanistically,
CD8
+
T
cells
promote
the
progressive
accumulation
abnormally
interferon-activated
microglia
display
myelin-damaging
activity.
Thus,
our
data
suggest
immune
responses
against
myelinating
oligodendrocytes
may
contribute
to
neurodegenerative
diseases
with
amyloidosis.
Clinical Epigenetics,
Год журнала:
2025,
Номер
17(1)
Опубликована: Янв. 24, 2025
Enriched
environment
(EE),
as
a
non-pharmacological
intervention,
has
garnered
considerable
attention
for
its
potential
to
ameliorate
neurodegenerative
diseases
(NDs).
This
review
delineated
the
impact
of
EE
on
biological
functions
associated
with
NDs,
emphasizing
role
in
enhancing
neural
plasticity,
reducing
inflammation,
and
bolstering
cognitive
performance.
We
discussed
molecular
underpinnings
effects
EE,
including
modulation
key
signaling
pathways
such
extracellular
regulated
kinase
1/2
(ERK1/2),
mitogen-activated
protein
kinases
(MAPK),
AMPK/SIRT1,
which
were
implicated
neuroprotection
synaptic
plasticity.
Additionally,
we
scrutinized
influence
epigenetic
modifications
autophagy,
processes
pivotal
ND
pathogenesis.
Animal
models,
encompassing
both
rodents
larger
animals,
offer
insights
into
disease-modifying
underscoring
complementary
approach
pharmacological
interventions.
In
summary,
emerges
promising
strategy
augment
function
decelerate
progression
NDs.
