EBioMedicine,
Journal Year:
2025,
Volume and Issue:
112, P. 105557 - 105557
Published: Jan. 31, 2025
Synapse
preservation
is
key
for
healthy
cognitive
ageing,
and
synapse
loss
represents
a
critical
anatomical
basis
of
dysfunction
in
Alzheimer's
disease
(AD),
predicting
dementia
onset,
severity,
progression.
viewed
as
primary
pathologic
event,
preceding
neuronal
brain
atrophy
AD.
Synapses
may,
therefore,
represent
one
the
earliest
clinically
most
meaningful
targets
neuropathologic
processes
driving
AD
dementia.
The
highly
selective
particularly
vulnerable
synapses
while
leaving
others,
termed
resilient,
largely
unaffected.
Yet,
anatomic
molecular
hallmarks
resilient
populations
their
association
with
changes
(e.g.
amyloid-β
plaques
tau
tangles)
memory
remain
poorly
understood.
Characterising
selectively
may
be
to
understanding
mechanisms
versus
enable
development
robust
biomarkers
disease-modifying
therapies
Signal Transduction and Targeted Therapy,
Journal Year:
2024,
Volume and Issue:
9(1)
Published: Aug. 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.
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.
Journal of Neuroimmunology,
Journal Year:
2024,
Volume and Issue:
390, P. 578342 - 578342
Published: April 5, 2024
Alzheimer's
disease
(AD)
is
a
neurodegenerative
characterized
by
cognitive
decline
that
severely
affects
patients
and
their
families.
Genetic
environmental
risk
factors,
such
as
viral
infections,
synergize
to
accelerate
the
aging-associated
neurodegeneration.
factors
for
late-onset
AD
(LOAD),
which
accounts
most
cases,
are
predominantly
implicated
in
microglial
immune
cell
functions.
As
such,
microglia
play
major
role
amyloid
beta
(Aβ)
plaque
(the
pathological
hallmark
of
AD)
formation.
This
review
aims
provide
an
overview
current
knowledge
regarding
Aβ
formation,
well
impact
on
morphological
functional
diversity
plaques.
Based
this
discussion,
we
seek
identify
challenges
opportunities
field
with
potential
therapeutic
implications.
Science Advances,
Journal Year:
2025,
Volume and Issue:
11(1)
Published: Jan. 3, 2025
Alzheimer’s
disease
(AD)
is
the
leading
dementia
among
elderly
with
complex
origins.
Despite
extensive
investigation
into
AD-associated
protein-coding
genes,
involvement
of
noncoding
RNAs
(ncRNAs)
and
posttranscriptional
modification
(PTM)
in
AD
pathogenesis
remains
unclear.
Here,
we
comprehensively
characterized
landscape
ncRNAs
PTM
events
1460
samples
across
six
brain
regions
sourced
from
Mount
Sinai/JJ
Peters
VA
Medical
Center
Brain
Bank
Study
Mayo
cohorts,
encompassing
33,321
long
ncRNAs,
92,897
enhancer
RNAs,
53,763
alternative
polyadenylation
events,
900,221
A-to-I
RNA
editing
events.
We
additionally
identified
25,351
aberrantly
expressed
altered
associated
traits
further
corresponding
genes
to
construct
regulatory
networks.
Furthermore,
developed
a
user-friendly
data
portal,
ADatlas,
facilitating
users
exploring
our
results.
Our
study
aims
establish
comprehensive
platform
for
PTMs
advance
related
research.
International Journal of Molecular Sciences,
Journal Year:
2023,
Volume and Issue:
24(17), P. 13033 - 13033
Published: Aug. 22, 2023
Neurodegenerative
diseases
(NDs)
are
a
diverse
group
of
disorders
characterized
by
the
progressive
degeneration
and
death
neurons,
leading
to
range
neurological
symptoms.
Despite
heterogeneity
these
conditions,
common
denominator
is
implication
mitochondrial
dysfunction
in
their
pathogenesis.
Mitochondria
play
crucial
role
creating
biomolecules,
providing
energy
through
adenosine
triphosphate
(ATP)
generated
oxidative
phosphorylation
(OXPHOS),
producing
reactive
oxygen
species
(ROS).
When
they’re
not
functioning
correctly,
becoming
fragmented
losing
membrane
potential,
they
contribute
diseases.
In
this
review,
we
explore
how
mitochondria
fuse
undergo
fission,
especially
context
NDs.
We
discuss
genetic
protein
mutations
linked
impact
dynamics.
also
look
at
key
regulatory
proteins
fusion
(MFN1,
MFN2,
OPA1)
fission
(DRP1
FIS1),
including
post-translational
modifications.
Furthermore,
highlight
potential
drugs
that
can
influence
By
unpacking
complex
processes,
aim
direct
research
towards
treatments
improve
life
quality
for
people
with
challenging
conditions.
Current Opinion in Structural Biology,
Journal Year:
2024,
Volume and Issue:
85, P. 102776 - 102776
Published: Feb. 8, 2024
The
complex
molecular
mechanism
and
pathophysiology
of
Alzheimer's
disease
(AD)
limits
the
development
effective
therapeutics
or
prevention
strategies.
Artificial
Intelligence
(AI)-guided
drug
discovery
combined
with
genetics/multi-omics
(genomics,
epigenomics,
transcriptomics,
proteomics,
metabolomics)
analysis
contributes
to
understanding
precision
medicine
disease,
including
AD
AD-related
dementia.
In
this
review,
we
summarize
AI-driven
methodologies
for
AD-agnostic
development,
de
novo
design,
virtual
screening,
prediction
drug-target
interactions,
all
which
have
shown
potentials.
particular,
AI-based
repurposing
emerges
as
a
compelling
strategy
identify
new
indications
existing
drugs
AD.
We
provide
several
emerging
targets
from
human
genetics
multi-omics
findings
highlight
recent
technologies
their
applications
in
using
prototypical
example.
closing,
discuss
future
challenges
directions
other
neurodegenerative
diseases.
Journal of Neurology,
Journal Year:
2024,
Volume and Issue:
271(6), P. 2992 - 3018
Published: March 30, 2024
Abstract
Tauopathies
are
a
heterogeneous
group
of
neurologic
diseases
characterized
by
pathological
axodendritic
distribution,
ectopic
expression,
and/or
phosphorylation
and
aggregation
the
microtubule-associated
protein
TAU,
encoded
gene
MAPT
.
Neuronal
dysfunction,
dementia,
neurodegeneration
common
features
these
often
detrimental
diseases.
A
neurodegenerative
disease
is
considered
primary
tauopathy
when
mutations/haplotypes
its
cause
TAU
main
feature.
In
case
pathology
observed
but
superimposed
another
hallmark,
condition
classified
as
secondary
tauopathy.
some
tauopathies
(e.g.
-associated
frontotemporal
dementia
(FTD),
progressive
supranuclear
palsy
(PSP),
corticobasal
degeneration
(CBD),
Alzheimer's
(AD))
recognized
significant
pathogenic
driver
disease.
many
tauopathies,
including
Parkinson's
(PD)
Huntington's
(HD),
suggested
to
contribute
development
in
others
Niemann-Pick
(NPC))
may
only
be
bystander.
The
genetic
mechanisms
underlying
not
fully
understood.
this
review,
predispositions
variants
associated
with
both
examined
detail,
assessing
evidence
for
role
conditions.
We
highlight
less
forms
increase
awareness
disorders
involvement
their
pathology.
This
approach
contributes
deeper
understanding
conditions
also
lay
groundwork
potential
TAU-based
therapeutic
interventions
various
tauopathies.
