Molecular Brain,
Journal Year:
2025,
Volume and Issue:
18(1)
Published: Feb. 10, 2025
Abstract
The
microenvironment
of
the
central
nervous
system
is
highly
complex
and
plays
a
crucial
role
in
maintaining
function
neurons,
which
influences
Alzheimer’s
disease
(AD)
progression.
pH
value
brain
critical
aspect
regulating
various
physiological
processes.
However,
specific
mechanisms
this
mechanism
are
not
yet
fully
understood.
To
better
understand
relationship
between
AD,
we
analyzed
frontal
lobe
AD
pathology
scores
postmortem
samples
from
368
donors
National
Human
Brain
Bank
for
Development
Function,
96
whom
were
diagnosed
with
pathology.
Analysis
revealed
significant
decrease
patients,
was
strongly
correlated
β-amyloid
plaques
phosphorylated
tau
proteins.
Here,
elucidated
differential
protein
expression
level
CD68-positive
microglia
control
groups
(t
=
3.198,
df
20,
P
0.0045),
its
negatively
(F
26.93,
p
0.0006).
Our
findings
that
increased
activation
disrupted
lysosomal
homeostasis
pathological
tissue
individuals
may
lead
to
pH.
Pharmaceuticals,
Journal Year:
2024,
Volume and Issue:
17(5), P. 612 - 612
Published: May 10, 2024
Overcoming
the
blood–brain
barrier
(BBB)
remains
a
significant
hurdle
in
effective
drug
delivery
to
brain.
While
BBB
serves
as
crucial
protective
barrier,
it
poses
challenges
delivering
therapeutic
agents
their
intended
targets
within
brain
parenchyma.
To
enhance
for
treatment
of
neurological
diseases,
several
technologies
circumvent
have
been
developed
last
few
years.
Among
them,
nanoparticles
(NPs)
are
one
most
versatile
and
promising
tools.
Here,
we
summarize
characteristics
NPs
that
facilitate
penetration,
including
size,
shape,
chemical
composition,
surface
charge,
importantly,
conjugation
with
various
biological
or
synthetic
molecules
such
glucose,
transferrin,
insulin,
polyethylene
glycol,
peptides,
aptamers.
Additionally,
discuss
coating
surfactants.
A
comprehensive
overview
common
vitro
vivo
models
NP
penetration
studies
is
also
provided.
The
discussion
extends
discussing
impairment
under
pathological
conditions
leveraging
alterations
delivery.
Emphasizing
need
future
uncover
inherent
properties
NPs,
review
advocates
role
beyond
systems
calls
efforts
translating
clinic
therapeutics.
Overall,
stand
out
highly
strategy
precise
targeting
disorders.
Annual Review of Immunology,
Journal Year:
2024,
Volume and Issue:
42(1), P. 585 - 613
Published: March 1, 2024
Alzheimer
disease
(AD)
is
the
most
common
neurodegenerative
disease,
and
with
no
efficient
curative
treatment
available,
its
medical,
social,
economic
burdens
are
expected
to
dramatically
increase.
AD
historically
characterized
by
amyloid
β
(Aβ)
plaques
tau
neurofibrillary
tangles,
but
over
last
25
years
chronic
immune
activation
has
been
identified
as
an
important
factor
contributing
pathogenesis.
In
this
article,
we
review
recent
advances
in
our
understanding
of
significance
development
AD.
We
describe
how
brain-resident
macrophages,
microglia,
able
detect
Aβ
species
be
activated,
well
consequences
activated
microglia
discuss
transcriptional
changes
AD,
their
unique
heterogeneity
humans,
emerging
strategies
study
human
microglia.
Finally,
expose,
beyond
role
peripheral
signals
different
cell
types
activation.
Frontiers in Endocrinology,
Journal Year:
2025,
Volume and Issue:
15
Published: Jan. 17, 2025
Obesity
is
a
major
modifiable
risk
factor
leading
to
neuroinflammation
and
neurodegeneration.
Excessive
fat
storage
in
obesity
promotes
the
progressive
infiltration
of
immune
cells
into
adipose
tissue,
resulting
release
pro-inflammatory
factors
such
as
cytokines
adipokines.
These
inflammatory
mediators
circulate
through
bloodstream,
propagating
inflammation
both
periphery
central
nervous
system.
Gut
dysbiosis,
which
results
leaky
intestinal
barrier,
exacerbates
plays
significant
role
linking
pathogenesis
neurodegeneration
gut-brain/gut-brain-liver
axis.
Inflammatory
states
within
brain
can
lead
insulin
resistance,
mitochondrial
dysfunction,
autolysosomal
increased
oxidative
stress.
disruptions
impair
normal
neuronal
function
subsequently
cognitive
decline
motor
deficits,
similar
pathologies
observed
neurodegenerative
diseases,
including
Alzheimer's
disease,
multiple
sclerosis,
Parkinson's
disease.
Understanding
underlying
disease
mechanisms
crucial
for
developing
therapeutic
strategies
address
defects
these
metabolic
pathways.
In
this
review,
we
summarize
provide
insights
different
strategies,
methods
alter
gut
lifestyle
changes,
dietary
supplementation,
well
pharmacological
agents
derived
from
natural
sources,
that
target
obesity-induced
Biomedicines,
Journal Year:
2025,
Volume and Issue:
13(2), P. 279 - 279
Published: Jan. 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
Cell Reports,
Journal Year:
2025,
Volume and Issue:
44(1), P. 115204 - 115204
Published: Jan. 1, 2025
Neuraminidase
1
(NEU1)
cleaves
terminal
sialic
acids
from
sialoglycoproteins
in
endolysosomes
and
at
the
plasma
membrane.
As
such,
NEU1
regulates
immune
cells,
primarily
those
of
monocytic
lineage.
Here,
we
examine
how
Neu1
influences
microglia
by
modulating
sialylation
full-length
Trem2
(Trem2-FL),
a
multifunctional
receptor
that
microglial
survival,
phagocytosis,
cytokine
production.
When
is
deficient/downregulated,
Trem2-FL
remains
sialylated,
accumulates
intracellularly,
excessively
cleaved
into
C-terminal
fragment
(Trem2-CTF)
an
extracellular
soluble
domain
(sTrem2),
enhancing
their
signaling
capacities.
Sialylated
(Sia-Trem2-FL)
does
not
hinder
Trem2-FL-DAP12-Syk
complex
assembly
but
impairs
signal
transduction
through
Syk,
ultimately
abolishing
Trem2-dependent
phagocytosis.
Concurrently,
Trem2-CTF-DAP12
complexes
dampen
NF-κB
signaling,
while
sTrem2
propagates
Akt-dependent
cell
survival
NFAT1-mediated
production
TNF-α
CCL3.
Because
are
implicated
neurodegenerative/neuroinflammatory
diseases,
including
Alzheimer
disease
sialidosis,
activity
represents
therapeutic
approach
to
broadly
regulate
microglia-mediated
neuroinflammation.
International Journal of Molecular Sciences,
Journal Year:
2024,
Volume and Issue:
25(13), P. 6901 - 6901
Published: June 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.
Neural Regeneration Research,
Journal Year:
2024,
Volume and Issue:
20(4), P. 1069 - 1076
Published: May 17, 2024
The
interaction
between
metabolic
dysfunction
and
inflammation
is
central
to
the
development
of
neurodegenerative
diseases
such
as
Alzheimer’s
disease
Parkinson’s
disease.
Obesity-related
conditions
like
type
2
diabetes
non-alcoholic
fatty
liver
exacerbate
this
relationship.
Peripheral
lipid
accumulation,
particularly
in
liver,
initiates
a
cascade
inflammatory
processes
that
extend
brain,
influencing
critical
regulatory
regions.
Ceramide
palmitate,
key
components,
along
with
transporters
lipocalin-2
apolipoprotein
E,
contribute
neuroinflammation
by
disrupting
blood–brain
barrier
integrity
promoting
gliosis.
insulin
resistance
further
exacerbates
brain
neuroinflammation.
Preclinical
interventions
targeting
peripheral
metabolism
signaling
pathways
have
shown
promise
reducing
animal
models.
However,
translating
these
findings
clinical
practice
requires
investigation
into
human
subjects.
In
conclusion,
dysfunction,
inflammation,
are
integral
neurodegeneration.
Understanding
complex
mechanisms
holds
potential
for
identifying
novel
therapeutic
targets
improving
outcomes
diseases.
ACS Nano,
Journal Year:
2024,
Volume and Issue:
18(24), P. 15452 - 15467
Published: June 3, 2024
Type
2
diabetes
(T2D),
a
prevalent
metabolic
disorder
lacking
effective
treatments,
is
associated
with
lysosomal
acidification
dysfunction,
as
well
autophagic
and
mitochondrial
impairments.
Here,
we
report
series
of
biodegradable
poly(butylene
tetrafluorosuccinate-co-succinate)
polyesters,
comprising
1,4-butanediol
linker
varying
ratios
tetrafluorosuccinic
acid
(TFSA)
succinic
components,
to
engineer
lysosome-acidifying
nanoparticles
(NPs).
The
synthesized
NPs
are
spherical
diameters
≈100
nm
have
low
polydispersity
good
stability.
Notably,
TFSA
NPs,
which
composed
entirely
TFSA,
exhibit
the
strongest
degradation
capability
superior
acidifying
properties.
We
further
reveal
significant
downregulation
vacuolar
(H+)-ATPase
subunits,
responsible
for
maintaining
acidification,
in
human
T2D
pancreatic
islets,
INS-1
β-cells
under
chronic
lipotoxic
conditions,
tissues
high-fat-diet
(HFD)
mice.
Treatment
restores
function,
activity,
thereby
improving
function
cells
HFD
mice
lipid
overload.
Importantly,
administration
reduces
insulin
resistance
improves
glucose
clearance.
These
findings
highlight
therapeutic
potential
T2D.
Journal of Neuroinflammation,
Journal Year:
2025,
Volume and Issue:
22(1)
Published: March 10, 2025
Abstract
Astrocytes
are
a
major
cell
type
in
the
central
nervous
system
(CNS)
that
play
key
role
regulating
homeostatic
functions,
responding
to
injuries,
and
maintaining
blood-brain
barrier.
also
regulate
neuronal
functions
survival
by
modulating
myelination
degradation
of
pathological
toxic
protein
aggregates.
have
recently
been
proposed
possess
both
autophagic
activity
active
phagocytic
capability
which
largely
depend
on
sufficiently
acidified
lysosomes
for
complete
cellular
cargos.
Defective
lysosomal
acidification
astrocytes
impairs
their
resulting
accumulation
debris,
excessive
myelin
lipids,
aggregates,
ultimately
contributes
propagation
neuroinflammation
neurodegenerative
pathology.
Restoration
impaired
represent
new
neuroprotective
strategy
therapeutic
direction.
In
this
review,
we
summarize
pathogenic
factors,
including
neuroinflammatory
signaling,
metabolic
stressors,
lipid
mediated
toxicity,
contribute
impairment
associated
dysfunction
astrocytes.
We
discuss
astrocyte-mediated
primarily
context
diseases
along
with
other
brain
injuries.
then
highlight
re-acidification
as
restore
well
degradative
capacity
conclude
providing
future
perspectives
phagocytes
crosstalk
CNS
cells
impart
or
effects.