Frontiers in Cell and Developmental Biology,
Год журнала:
2023,
Номер
11
Опубликована: Ноя. 8, 2023
Triggering
receptor
expressed
on
myeloid
cells
2
(TREM2),
a
pattern
recognition
abundantly
microglia,
has
been
identified
as
one
of
the
risk
factors
for
Alzheimer’s
disease
(AD).
Several
studies
have
already
demonstrated
relationship
between
TREM2
and
Tau.
mutations
altered
expression
play
an
important
role
in
Tau
phosphorylation.
Furthermore,
level
phosphorylation
is
correlated
with
soluble
(sTREM2).
However,
different
stages
AD,
seems
to
varying
effects
pathology.
The
explicit
interaction
Tau,
well
how
they
affect
AD
pathology,
remains
unclear,
there
much
evidence
contrary
that
requires
rational
interpretation.
Reviewing
dual
roles
will
help
identify
more
appropriate
development
strategy
targeting
treat
AD.
Therefore,
this
review
focuses
interplay
relation
Signal Transduction and Targeted Therapy,
Год журнала:
2023,
Номер
8(1)
Опубликована: Июнь 30, 2023
Abstract
Amyloid
β
protein
(Aβ)
is
the
main
component
of
neuritic
plaques
in
Alzheimer’s
disease
(AD),
and
its
accumulation
has
been
considered
as
molecular
driver
pathogenesis
progression.
Aβ
prime
target
for
development
AD
therapy.
However,
repeated
failures
Aβ-targeted
clinical
trials
have
cast
considerable
doubt
on
amyloid
cascade
hypothesis
whether
drug
followed
correct
course.
recent
successes
targeted
assuaged
those
doubts.
In
this
review,
we
discussed
evolution
over
last
30
years
summarized
application
diagnosis
modification.
particular,
extensively
pitfalls,
promises
important
unanswered
questions
regarding
current
anti-Aβ
therapy,
well
strategies
further
study
more
feasible
approaches
optimization
prevention
treatment.
Nature Aging,
Год журнала:
2024,
Номер
4(1), С. 33 - 47
Опубликована: Янв. 9, 2024
Abstract
Alzheimer’s
disease
(AD)
is
heterogenous
at
the
molecular
level.
Understanding
this
heterogeneity
critical
for
AD
drug
development.
Here
we
define
subtypes
using
mass
spectrometry
proteomics
in
cerebrospinal
fluid,
based
on
1,058
proteins,
with
different
levels
individuals
(
n
=
419)
compared
to
controls
187).
These
had
alterations
protein
that
were
associated
distinct
processes:
subtype
1
was
characterized
by
proteins
related
neuronal
hyperplasticity;
2
innate
immune
activation;
3
RNA
dysregulation;
4
choroid
plexus
dysfunction;
and
5
blood–brain
barrier
impairment.
Each
specific
genetic
risk
variants,
example,
enriched
TREM2
R47H.
Subtypes
also
differed
clinical
outcomes,
survival
times
anatomical
patterns
of
brain
atrophy.
results
indicate
highlight
need
personalized
medicine.
Science,
Год журнала:
2024,
Номер
384(6701), С. 1220 - 1227
Опубликована: Май 16, 2024
Developing
vehicles
that
efficiently
deliver
genes
throughout
the
human
central
nervous
system
(CNS)
will
broaden
range
of
treatable
genetic
diseases.
We
engineered
an
adeno-associated
virus
(AAV)
capsid,
BI-hTFR1,
binds
transferrin
receptor
(TfR1),
a
protein
expressed
on
blood-brain
barrier.
BI-hTFR1
was
actively
transported
across
brain
endothelial
cells
and,
relative
to
AAV9,
provided
40
50
times
greater
reporter
expression
in
CNS
Translational Neurodegeneration,
Год журнала:
2024,
Номер
13(1)
Опубликована: Фев. 20, 2024
Abstract
Brain
aging
is
a
recognized
risk
factor
for
neurodegenerative
diseases
like
Alzheimer's
disease,
Parkinson's
and
amyotrophic
lateral
sclerosis
(ALS,
Lou
Gehrig's
disease),
but
the
intricate
interplay
between
brain
pathogenesis
of
these
conditions
remains
inadequately
understood.
Cellular
senescence
considered
to
contribute
cellular
dysfunction
inflammaging.
According
threshold
theory
senescent
cell
accumulation,
vulnerability
associated
with
rates
generation
clearance
within
brain.
Given
role
microglia
in
eliminating
cells,
accumulation
may
lead
acceleration
aging,
contributing
inflammaging
increased
diseases.
In
this
review,
we
propose
idea
that
microglia,
which
notably
vulnerable
could
potentially
serve
as
central
catalyst
progression
The
are
emerging
promising
target
mitigating
Nature Communications,
Год журнала:
2024,
Номер
15(1)
Опубликована: Март 12, 2024
Abstract
Developing
diagnostics
and
treatments
for
neurodegenerative
diseases
(NDs)
is
challenging
due
to
multifactorial
pathogenesis
that
progresses
gradually.
Advanced
in
vitro
systems
recapitulate
patient-like
pathophysiology
are
emerging
as
alternatives
conventional
animal-based
models.
In
this
review,
we
explore
the
interconnected
pathogenic
features
of
different
types
ND,
discuss
general
strategy
modelling
NDs
using
a
microfluidic
chip,
introduce
organoid-on-a-chip
next
advanced
relevant
model.
Lastly,
overview
how
these
models
being
applied
academic
industrial
drug
development.
The
integration
chips,
stem
cells,
biotechnological
devices
promises
provide
valuable
insights
biomedical
research
developing
diagnostic
therapeutic
solutions
NDs.
Ageing Research Reviews,
Год журнала:
2024,
Номер
94, С. 102192 - 102192
Опубликована: Янв. 14, 2024
Alzheimer's
disease
(AD)
is
the
most
common
neurodegenerative
characterized
by
cognitive
impairment
with
few
therapeutic
options.
Despite
many
failures
in
developing
AD
treatment
during
past
20
years,
significant
advances
have
been
achieved
passive
immunotherapy
of
very
recently.
Here,
we
review
characteristics,
clinical
trial
data,
and
mechanisms
action
for
monoclonal
antibodies
(mAbs)
targeting
key
players
pathogenesis,
including
amyloid-β
(Aβ),
tau
neuroinflammation
modulators.
We
emphasized
efficacy
lecanemab
donanemab
on
cognition
amyloid
clearance
patients
phase
III
trials
discussed
factors
that
may
contribute
to
side
effects
anti-Aβ
mAbs.
In
addition,
provided
important
information
mAbs
or
inflammatory
regulators
trials,
indicated
against
mid-region
pathogenic
potential
AD.
conclusion,
pathogenesis
offers
a
promising
strategy
effective
treatment.
ACS Nano,
Год журнала:
2024,
Номер
18(18), С. 11753 - 11768
Опубликована: Апрель 22, 2024
The
association
between
dysfunctional
microglia
and
amyloid-β
(Aβ)
is
a
fundamental
pathological
event
increases
the
speed
of
Alzheimer's
disease
(AD).
Additionally,
pathogenesis
AD
intricate
single
drug
may
not
be
enough
to
achieve
satisfactory
therapeutic
outcome.
Herein,
we
reported
facile
effective
gene
therapy
strategy
for
modulation
function
intervention
Aβ
anabolism
by
ROS-responsive
biomimetic
exosome-liposome
hybrid
nanovesicles
(designated
as
TSEL).
codelivery
β-site
amyloid
precursor
protein
cleaving
enzyme-1
(BACE1)
siRNA
(siBACE1)
TREM2
plasmid
(pTREM2)
efficiently
penetrate
blood-brain
barrier
enhance
accumulation
at
lesions
with
help
exosomes
homing
ability
angiopep-2
peptides.
Specifically,
an
upregulation
expression
can
reprogram
from
pro-inflammatory
M1
phenotype
anti-inflammatory
M2
while
also
restoring
its
capacity
phagocytose
nerve
repair
function.
In
addition,
reduces
production
plaques
source
knocking
out
BACE1
gene,
which
expected
further
effect
AD.
in
vivo
study
suggests
that
TSEL
through
synergistic
two
drugs
ameliorate
APP/PS1
mice
cognitive
impairment
regulating
activated
microglial
phenotype,
reducing
Aβ,
preventing
retriggering
neuroinflammation.
This
employs
delivery
dual
nucleic
acids,
achieving
AD,
thus
offering
more
options
treatment
Science Translational Medicine,
Год журнала:
2024,
Номер
16(760)
Опубликована: Авг. 14, 2024
Antisense
oligonucleotides
(ASOs)
are
promising
therapeutics
for
treating
various
neurological
disorders.
However,
ASOs
unable
to
readily
cross
the
mammalian
blood-brain
barrier
(BBB)
and
therefore
need
be
delivered
intrathecally
central
nervous
system
(CNS).
Here,
we
engineered
a
human
transferrin
receptor
1
(TfR1)
binding
molecule,
oligonucleotide
transport
vehicle
(OTV),
tool
ASO
across
BBB
in
TfR
knockin
(TfR
mu/hu
KI)
mice
nonhuman
primates.
Intravenous
injection
systemic
delivery
of
OTV
KI
resulted
sustained
knockdown
target
RNA,
Malat1
,
multiple
mouse
CNS
regions
cell
types,
including
endothelial
cells,
neurons,
astrocytes,
microglia,
oligodendrocytes.
In
addition,
enabled
RNA
quadriceps
cardiac
muscles,
which
difficult
with
alone.
Systemically
more
uniform
biodistribution
profile
greater
compared
bivalent,
high-affinity
antibody.
cynomolgus
macaques,
an
directed
against
MALAT1
displayed
robust
primate
intrathecal
dosing
same
unconjugated
ASO.
Our
data
support
systemically
as
potential
platform
delivering
therapeutic
BBB.
Neurobiology of Disease,
Год журнала:
2024,
Номер
196, С. 106505 - 106505
Опубликована: Апрель 19, 2024
Alzheimer's
and
Parkinson's
diseases
are
two
of
the
most
frequent
neurological
diseases.
The
clinical
features
AD
memory
decline
cognitive
dysfunction,
while
PD
mainly
manifests
as
motor
dysfunction
such
limb
tremors,
muscle
rigidity
abnormalities,
slow
gait.
Abnormalities
in
cholesterol,
sphingolipid,
glycerophospholipid
metabolism
have
been
demonstrated
to
directly
exacerbate
progression
by
stimulating
Aβ
deposition
tau
protein
tangles.
Indirectly,
abnormal
lipids
can
increase
burden
on
brain
vasculature,
induce
insulin
resistance,
affect
structure
neuronal
cell
membranes.
Abnormal
lipid
leads
through
inducing
accumulation
α-syn,
mitochondria
endoplasmic
reticulum,
ferroptosis.
Great
progress
has
made
targeting
abnormalities
for
treatment
recent
years,
like
metformin,
insulin,
peroxisome
proliferator-activated
receptors
(PPARs)
agonists,
monoclonal
antibodies
apolipoprotein
E
(ApoE).
This
review
comprehensively
summarizes
involvement
dysregulated
pathogenesis
PD,
application
Lipid
Monitoring,
emerging
regulatory
drug
targets.
A
better
understanding
lipidological
bases
may
pave
way
developing
effective
prevention
methods
neurodegenerative
disorders.
