bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2023,
Номер
unknown
Опубликована: Дек. 12, 2023
Abstract
Microglia,
the
immune
cells
of
central
nervous
system
(CNS),
are
incredibly
dynamic
and
heterogenous
cells.
While
single
cell
RNA
sequencing
has
become
conventional
methodology
for
evaluating
microglial
state,
transcriptomics
do
not
provide
insight
into
functional
changes.
Here,
we
propose
a
novel
organelle
phenotyping
approach
where
treat
live
human
induced
pluripotent
stem
cell-derived
microglia
(iMGL)
with
dyes
(mitochondria,
lipids,
lysosomes)
acquire
data
by
live-cell
spectral
microscopy.
Dimensionality
reduction
techniques
unbiased
cluster
identification
allow
recognition
subpopulations
based
in
function.
We
validate
this
using
lipopolysaccharide
(LPS)
IL-10
treatment
to
polarize
iMGL
an
inflammatory”
“anti-inflammatory
respectively,
then
apply
it
identify
regulator
function,
complement
protein
C1q.
C1q
is
traditionally
known
as
initiator
cascade,
but
here
use
role
regulating
fatty
acid
storage
mitochondria
membrane
potential.
Follow
up
evaluation
more
traditional
read
outs
activation
state
confirm
that
drives
increase
pro-inflammatory
cytokine
production
migration,
while
suppressing
proliferation.
These
together
enable
better
mechanism
investigation
molecular
regulators
such
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.
International Journal of Molecular Sciences,
Год журнала:
2024,
Номер
25(2), С. 817 - 817
Опубликована: Янв. 9, 2024
As
an
essential
component
of
our
innate
immune
system,
the
complement
system
is
responsible
for
defense
against
pathogens.
The
cascade
has
complex
roles
in
central
nervous
(CNS),
most
what
we
know
about
it
stems
from
its
role
brain
development.
However,
recent
years,
numerous
reports
have
implicated
classical
both
development
and
decline.
More
specifically,
dysfunction
been
neurodegenerative
disorders,
such
as
Alzheimer's
disease
(AD),
which
common
form
dementia.
Synapse
loss
one
main
pathological
hallmarks
AD
correlates
with
memory
impairment.
Throughout
course
progression,
synapses
are
tagged
proteins
consequently
removed
by
microglia
that
express
receptors.
Notably,
astrocytes
also
capable
secreting
signals
induce
expression
CNS.
Both
neuroinflammation,
another
hallmark
pathogenesis.
In
this
review,
provide
overview
previously
known
newly
established
CNS
explore
how
interactions
microglia,
astrocytes,
other
risk
factors
TREM2
ApoE4
modulate
processes
neurodegeneration
amyloid
tau
models
AD.
Journal of Extracellular Vesicles,
Год журнала:
2023,
Номер
12(12)
Опубликована: Дек. 1, 2023
Abstract
Dementia
is
a
leading
cause
of
death
worldwide,
with
increasing
prevalence
as
global
life
expectancy
increases.
The
most
common
neurodegenerative
disorders
are
Alzheimer's
disease
(AD),
dementia
Lewy
bodies
(DLB)
and
Parkinson's
(PDD).
With
this
study,
we
took
an
in‐depth
look
at
the
proteome
(non‐purified)
cerebrospinal
fluid
(CSF)
CSF‐derived
extracellular
vesicles
(EVs)
AD,
PD,
PD‐MCI
(Parkinson's
mild
cognitive
impairment),
PDD
DLB
patients
analysed
by
label‐free
mass
spectrometry.
This
has
led
to
discovery
differentially
expressed
proteins
that
may
be
helpful
for
differential
diagnosis.
We
observed
greater
number
in
EV
samples
(
N
=
276)
compared
non‐purified
CSF
169),
minimal
overlap
between
both
datasets.
finding
suggests
more
suitable
phase
biomarker
due
removal
abundant
proteins,
resulting
narrower
dynamic
range.
As
disease‐specific
markers,
selected
total
39
candidates
identified
CSF,
37
across
different
diseases
under
investigation
data.
After
further
exploration
validation
these
they
can
used
differentiate
included
dementias
offer
new
avenues
research
into
pharmacological
therapeutics.
Neurobiology of Disease,
Год журнала:
2025,
Номер
unknown, С. 106817 - 106817
Опубликована: Янв. 1, 2025
S100
calcium-binding
protein
A9
(S100A9,
also
known
as
calgranulin
B)
is
expressed
and
secreted
by
myeloid
cells
under
inflammatory
conditions,
S100A9
can
amplify
inflammation.
There
a
large
increase
in
expression
the
brains
of
patients
with
neurodegenerative
diseases,
such
Alzheimer's
disease,
has
been
suggested
to
contribute
neurodegeneration,
but
mechanisms
are
unclear.
Here
we
investigated
effects
extracellular
recombinant
on
microglia,
neurons
synapses
primary
rat
brain
neuronal-glial
cell
cultures.
Incubation
cultures
250-500
nM
caused
neuronal
loss
without
signs
apoptosis
or
necrosis,
accompanied
exposure
"eat-me"
signal
-
phosphatidylserine
neurons.
activation
microglial
inflammation
evidenced
an
number,
morphological
changes,
release
pro-inflammatory
cytokines,
increased
phagocytic
activity.
At
lower
concentrations,
10-100
induced
synaptic
Depletion
microglia
from
prevented
S100A9-induced
loss,
indicating
that
was
mediated
microglia.
These
results
suggest
may
neurodegeneration
activating
phagocytosis,
resulting
This
further
suggests
possibility
be
reduced
targeting
Frontiers in Neurology,
Год журнала:
2024,
Номер
15
Опубликована: Июль 3, 2024
Neurodegenerative
and
neuroinflammatory
diseases,
including
Alzheimer’s
disease,
Parkinson’s
multiple
sclerosis,
affect
millions
of
people
globally.
As
aging
is
a
major
risk
factor
for
neurodegenerative
the
continuous
increase
in
elderly
population
across
Western
societies
also
associated
with
rising
prevalence
these
debilitating
conditions.
The
complement
system,
crucial
component
innate
immune
response,
has
gained
increasing
attention
its
multifaceted
involvement
normal
development
central
nervous
system
(CNS)
brain
but
as
pathogenic
driver
several
disease
states.
Although
generally
understood
liver-derived
blood
or
interstitial
fluid
operative
protecting
against
bloodborne
pathogens
threats,
recent
research,
particularly
on
role
healthy
diseased
CNS,
demonstrated
importance
locally
produced
activated
components.
Here,
we
provide
succinct
overview
over
known
beneficial
pathological
roles
CNS
focus
local
sources
complement,
discussion
potential
recently
discovered
intracellularly
active
biology
infection-triggered
neurodegeneration.
Molecular Psychiatry,
Год журнала:
2024,
Номер
unknown
Опубликована: Сен. 3, 2024
Neuroimmune
interactions
play
a
significant
role
in
regulating
synaptic
plasticity
both
the
healthy
and
diseased
brain.
The
complement
pathway,
an
extracellular
proteolytic
cascade,
exemplifies
these
interactions.
Its
activation
triggers
microglia-dependent
elimination
via
receptor
3
(CR3).
Current
models
of
pathological
activity
brain
propose
that
accelerated
loss
resulting
from
overexpression
C4
(C4-OE),
gene
associated
with
schizophrenia,
follows
this
pathway.
Here,
we
report
C4-mediated
cortical
hypoconnectivity
is
CR3-independent.
Instead,
C4-OE
impaired
GluR1
trafficking
through
intracellular
mechanism
involving
endosomal
protein
SNX27,
loss.
Moreover,
circuit
alterations
prefrontal
cortex,
region
neuropsychiatric
disorders,
were
rescued
by
increasing
neuronal
levels
which
identify
as
interacting
partner
neuroimmune
protein.
Our
results
link
excessive
to
endo-lysosomal
pathway
altering
plasticity.
Journal of Nanobiotechnology,
Год журнала:
2024,
Номер
22(1)
Опубликована: Ноя. 6, 2024
Organoids
are
"mini-organs"
that
self-organize
and
differentiate
from
stem
cells
under
in
vitro
3D
culture
conditions,
mimicking
the
spatial
structure
function
of
tissues
vivo.
Extracellular
vesicles
(EVs)
nanoscale
phospholipid
bilayer
secreted
by
living
cells,
rich
bioactive
molecules,
with
excellent
biocompatibility
low
immunogenicity.
Compared
to
EVs,
organoid-derived
EVs
(OEVs)
exhibit
higher
yield
enhanced
biological
functions.
possess
cell
characteristics,
OEVs
capable
delivering
active
substances,
making
both
highly
promising
for
medical
applications.
In
this
review,
we
provide
an
overview
fundamental
principles
organoids
OEVs,
discuss
their
current
applications
disease
treatment.
We
then
focus
on
differences
between
traditional
EVs.
Subsequently,
present
methods
engineering
modification
OEVs.
Finally,
critically
summarize
advantages
challenges
conclusion,
believe
a
deeper
understanding
will
innovative
solutions
complex
diseases.
PubMed,
Год журнала:
2023,
Номер
4(4), С. 199 - 212
Опубликована: Янв. 1, 2023
With
the
rapid
development
of
population
ageing,
bone-related
diseases
seriously
affecting
life
elderly.
Over
past
few
years,
organoids,
cell
clusters
with
specific
functions
and
structures
that
are
self-induced
from
stem
cells
after
three-dimensional
culture
in
vitro,
have
been
widely
used
for
bone
therapy.
Moreover,
organoid
extracellular
vesicles
(OEVs)
emerging
as
promising
cell-free
nanocarriers
due
to
their
vigoroso
physiological
effects,
significant
biological
functions,
stable
loading
capacity,
great
biocompatibility.
In
this
review,
we
first
provide
a
comprehensive
overview
biogenesis,
internalisation,
isolation,
characterisation
OEVs.
We
then
comprehensively
highlight
differences
between
OEVs
traditional
EVs.
Subsequently,
present
applications
natural
disease
treatment.
also
summarise
engineering
modifications
OEVs,
including
parental
isolation.
an
outlook
on
potential
engineered
diseases.
Finally,
critically
discuss
advantages
challenges
treatment
believe
discussion
will
more
innovative
efficient
solutions
complex
