Synapse vulnerability and resilience underlying Alzheimer’s disease
EBioMedicine,
Год журнала:
2025,
Номер
112, С. 105557 - 105557
Опубликована: Янв. 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
Язык: Английский
An interim exploratory proteomics biomarker analysis of a phase 2 clinical trial to assess the impact of CT1812 in Alzheimer's disease
B.N. Lizama,
H.A. North,
Kiran Pandey
и другие.
Neurobiology of Disease,
Год журнала:
2024,
Номер
199, С. 106575 - 106575
Опубликована: Июнь 22, 2024
CT1812
is
a
novel,
brain
penetrant
small
molecule
modulator
of
the
sigma-2
receptor
(S2R)
that
currently
in
clinical
development
for
treatment
Alzheimer's
disease
(AD).
Preclinical
and
early
data
show
that,
through
S2R,
selectively
prevents
displaces
binding
amyloid
beta
(Aβ)
oligomers
from
neuronal
synapses
improves
cognitive
function
animal
models
AD.
SHINE
an
ongoing
Phase
2
randomized,
double-blind,
placebo-controlled
trial
(COG0201)
participants
with
mild
to
moderate
AD,
designed
assess
safety
efficacy
6
months
treatment.
To
elucidate
mechanism
action
AD
patients
pharmacodynamic
biomarkers
CT1812,
present
study
reports
exploratory
cerebrospinal
fluid
(CSF)
biomarker
18
interim
analysis
first
set
(part
A).
Untargeted
mass
spectrometry-based
discovery
proteomics
detects
>2000
proteins
patient
CSF
has
documented
utility
accelerating
identification
novel
reflective
diverse
pathophysiologies
beyond
tau,
enabling
longitudinal
interventional
trials.
We
leveraged
this
technique
analyze
samples
taken
at
baseline
after
Proteome-wide
protein
levels
were
detected
using
tandem
tag-mass
spectrometry
(TMT-MS),
change
was
calculated
each
participant,
differential
abundance
by
group
performed.
This
revealed
significantly
impacted
including
pathway
engagement
(i.e.,
tied
S2R
biology)
modification
altered
vs.
healthy
control
but
normalized
correlated
favorable
trends
ADAS-Cog11
scores).
Brain
network
mapping,
Gene
Ontology,
analyses
impact
on
synapses,
lipoprotein
biology,
neuroinflammation.
Collectively,
findings
highlight
method
providing
mechanistic
insights
which
may
facilitate
enable
appropriate
pre-specification
upcoming
trials
CT1812.
Язык: Английский
Which neuroimaging and fluid biomarkers method is better in theranostic of Alzheimer’s disease? An umbrella review
IBRO Neuroscience Reports,
Год журнала:
2024,
Номер
16, С. 403 - 417
Опубликована: Фев. 29, 2024
Язык: Английский
Roles of SIRT3 in cardiovascular and neurodegenerative diseases
Ageing Research Reviews,
Год журнала:
2025,
Номер
unknown, С. 102654 - 102654
Опубликована: Янв. 1, 2025
Язык: Английский
Sigma-2 receptor modulator CT1812 alters key pathways and rescues retinal pigment epithelium (RPE) functional deficits associated with dry age-related macular degeneration (AMD)
Scientific Reports,
Год журнала:
2025,
Номер
15(1)
Опубликована: Фев. 10, 2025
Trafficking
defects
in
retinal
pigmented
epithelial
(RPE)
cells
contribute
to
RPE
atrophy,
a
hallmark
of
geographic
atrophy
(GA)
dry
age-related
macular
degeneration
(AMD).
Dry
AMD
pathogenesis
is
multifactorial,
including
amyloid-β
(Aβ)
accumulation
and
oxidative
stress-common
features
Alzheimer's
disease
(AD).
The
Sigma-2
receptor
(S2R)
regulates
lipid
protein
trafficking,
S2R
modulators
reverse
trafficking
deficits
neurodegeneration
vitro
models.
Given
overlapping
mechanisms
contributing
AD
AMD,
modulator
effects
on
function
were
investigated.
CT1812
clinical
trials
for
AD,
dementia
with
Lewy
bodies,
GA.
Leveraging
testing
CT1812,
unbiased
analyses
patient
biofluid
proteomes
revealed
that
proteins
altered
by
associated
GA
ontologies
overlapped
AMD.
Differential
expression
analysis
transcripts
from
APP-Swedish/London
mutant
transgenic
mice,
model
featuring
Aβ
accumulation,
reversal
autophagy/trafficking
modulator-treated
animals
versus
vehicle
toward
healthy
control
levels.
Photoreceptor
outer
segment
(POS)
human
showed
response
Aβ1-42
or
hydrogen
peroxide
compared
vehicle.
normalized
stressor-induced
POS
deficits,
resembling
control.
Taken
together,
modulation
may
provide
novel
therapeutic
strategy
Язык: Английский
Positron Emission Tomography/Computed Tomography Imaging in Therapeutic Clinical Trials in Alzheimer’s Disease: An Overview of the Current State of the Art of Research
Journal of Alzheimer s Disease,
Год журнала:
2024,
Номер
101(s1), С. S603 - S628
Опубликована: Окт. 18, 2024
The
integration
of
positron
emission
tomography/computed
tomography
(PET/CT)
has
revolutionized
the
landscape
Alzheimer's
disease
(AD)
research
and
therapeutic
interventions.
By
combining
structural
functional
imaging,
PET/CT
provides
a
comprehensive
understanding
pathology
response
to
treatment
assessment.
PET/CT,
particularly
with
2-deoxy-2-[fluorine-18]fluoro-D-glucose
(18F-FDG),
facilitates
visualization
glucose
metabolism
in
brain,
enabling
early
diagnosis,
staging,
monitoring
neurodegenerative
progression.
advent
amyloid
tau
PET
imaging
further
propelled
field
forward,
offering
invaluable
tools
for
tracking
pathological
hallmarks,
assessing
response,
predicting
clinical
outcomes.
While
some
interventions
targeting
plaque
load
showed
promising
results
reduction
cerebral
accumulation
over
time,
others
failed
demonstrate
significant
impact
anti-amyloid
agents
reducing
plaques
burden
AD
brains.
Tau
conversely
fueled
disease-modifying
strategies
by
supporting
assessment
neurofibrillary
tangles
deposition
time.
Looking
ahead,
holds
immense
promise
studying
additional
targets
such
as
neuroinflammation,
cholinergic
deficit,
synaptic
dysfunction.
Advances
radiotracer
development,
dedicated
brain
scanners,
Artificial
Intelligence-powered
software
are
poised
enhance
quality,
sensitivity,
diagnostic
power
molecular
neuroimaging.
Consequently,
remains
at
forefront
research,
unparalleled
opportunities
unravelling
complexities
advancing
interventions,
although
it
is
not
yet
enough
alone
allow
patients'
recruitment
trials.
Язык: Английский
CT1812 biomarker signature from a meta‐analysis of CSF proteomic findings from two Phase 2 clinical trials in Alzheimer's disease
Alzheimer s & Dementia,
Год журнала:
2024,
Номер
unknown
Опубликована: Авг. 21, 2024
Abstract
INTRODUCTION
CT1812
is
in
clinical
development
for
the
treatment
of
Alzheimer's
disease
(AD).
Cerebrospinal
fluid
(CSF)
exploratory
proteomics
was
employed
to
identify
pharmacodynamic
biomarkers
mild
moderate
AD
from
two
independent
trials.
METHODS
Unbiased
analysis
tandem‐mass
tag
mass
spectrometry
(TMT‐MS)
quantitative
proteomics,
pathway
and
correlation
analyses
with
volumetric
magnetic
resonance
imaging
(vMRI)
were
performed
SPARC
cohort
(NCT03493282).
Comparative
a
meta‐analysis
interim
SHINE
(NCT03507790;
SHINE‐A)
followed
by
network
(weighted
gene
co‐expression
[WGCNA])
used
understand
biological
impact
CT1812.
RESULTS
pathways
identified
that
replicate
across
cohorts.
The
revealed
novel
candidate
linked
S2R
biology
AD,
treatment‐associated
networks
driven
S2R.
DISCUSSION
Early
validation
replicating
cohorts
strengthens
understanding
patients
supports
CT1812's
synaptoprotective
mechanism
action
its
continued
development.
Highlights
This
study
(NCT03493282)
trials/cohorts
Two
Ph2
trial
(SPARC
[NCT03507790;
SHINE‐A])
Amyloid
beta
(Aβ)
&
synaptic
impacted
treatment‐related
correlates
emerge
Network
sigma‐2
receptor
(S2R)‐interacting
proteins
may
be
“drivers”
changes
Язык: Английский
An interim exploratory biomarker analysis of a Phase 2 clinical trial to assess the impact of CT1812 in Alzheimer’s disease
B.N. Lizama,
H.A. North,
Kiran Pandey
и другие.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Фев. 21, 2024
ABSTRACT
CT1812
is
a
novel,
brain
penetrant
small
molecule
modulator
of
the
sigma-2
receptor
(S2R)
that
currently
in
clinical
development
for
treatment
Alzheimer’s
disease
(AD).
Preclinical
and
early
data
show
that,
through
S2R,
selectively
prevents
displaces
binding
amyloid
beta
(Aβ)
oligomers
from
neuronal
synapses
improves
cognitive
function
animal
models
AD.
SHINE
an
ongoing
Phase
2
randomized,
double-blind,
placebo-controlled
trial
(COG0201)
patients
with
mild
to
moderate
AD,
designed
assess
safety
efficacy
6
months
treatment.
To
elucidate
mechanism
action
AD
pharmacodynamic
biomarkers
CT1812,
present
study
reports
exploratory
cerebrospinal
fluid
(CSF)
biomarker
interim
analysis
first
set
(part
A).
Untargeted
mass
spectrometry-based
discovery
proteomics
can
detect
more
than
2,000
proteins
patient
CSF
has
documented
utility
accelerating
identification
novel
reflective
diverse
pathophysiologies
beyond
tau
enabling
longitudinal
interventional
trials.
We
leveraged
this
technique
analyze
samples
taken
at
baseline
after
Proteome-wide
protein
levels
were
detected
using
tandem
tag-mass
spectrometry
(TMT-MS),
change
was
calculated
each
participant,
differential
abundance
by
group
performed.
This
revealed
significantly
impacted
including
pathway
engagement
(i.e.,
tied
S2R
biology)
modification
altered
vs.
healthy
control
but
normalized
correlated
favorable
trends
ADAS-Cog11
scores).
Brain
network
mapping,
Gene
Ontology,
analyses
impact
on
synapses,
lipoprotein
biology,
neuroinflammation.
Collectively,
findings
highlight
method
providing
mechanistic
insights
which
may
facilitate
enable
appropriate
pre-specification
upcoming
trials
CT1812.
HIGHLIGHTS
Effects
investigated
randomized
Pharmacodynamic
identified
unbiased
quantitation
acquired
TMT
Mass
Spectrometry
(TMT-MS)
Findings
provide
proof
impacts
synapse,
inflammation,
amyloid-related
processes
Язык: Английский
Comparison of the efficacy of updated drugs for the treatment on the improvement of cognitive function in patients with Alzheimer ’s disease: A systematic review and network meta- analysis
Neuroscience,
Год журнала:
2024,
Номер
565, С. 29 - 39
Опубликована: Ноя. 15, 2024
Язык: Английский
Biomarker-Based Precision Therapy for Alzheimer’s Disease: Multidimensional Evidence Leading a New Breakthrough in Personalized Medicine
Journal of Clinical Medicine,
Год журнала:
2024,
Номер
13(16), С. 4661 - 4661
Опубликована: Авг. 8, 2024
(1)
Background:
Alzheimer’s
disease
(AD)
is
a
worldwide
neurodegenerative
disorder
characterized
by
the
buildup
of
abnormal
proteins
in
central
nervous
system
and
cognitive
decline.
Since
no
radical
therapy
exists,
only
symptomatic
treatments
alleviate
symptoms
temporarily.
In
this
review,
we
will
explore
latest
advancements
precision
medicine
biomarkers
for
AD,
including
their
potential
to
revolutionize
way
diagnose
treat
devastating
condition.
(2)
Methods:
A
literature
search
was
performed
combining
following
Medical
Subject
Heading
(MeSH)
terms
on
PubMed:
“Alzheimer’s
disease”,
“biomarkers”,
“APOE”,
“APP”,
“GWAS”,
“cerebrospinal
fluid”,
“polygenic
risk
score”,
“Aβ42”,
“τP-181”,
“
p-tau217”,
“ptau231”,
“proteomics”,
“total
tau
protein”,
“precision
medicine”
using
Boolean
operators.
(3)
Results:
Genome-wide
association
studies
(GWAS)
have
identified
numerous
genetic
variants
associated
with
AD
risk,
while
transcriptomic
analysis
has
revealed
dysregulated
gene
expression
patterns
brains
individuals
AD.
The
proteomic
metabolomic
profiling
biological
fluids,
such
as
blood,
urine,
CSF,
neuroimaging
also
yielded
that
could
be
used
early
diagnosis
monitoring
progression.
(4)
Conclusion:
By
leveraging
combination
above
biomarkers,
novel
ultrasensitive
immunoassays,
mass
spectrometry
methods,
metabolomics,
researchers
are
making
significant
strides
towards
personalized
healthcare
Язык: Английский