Trends in Molecular Medicine,
Год журнала:
2023,
Номер
29(8), С. 659 - 672
Опубликована: Июнь 22, 2023
Progression
of
Alzheimer's
disease
(AD)
entails
deterioration
or
aberrant
function
multiple
brain
cell
types,
eventually
leading
to
neurodegeneration
and
cognitive
decline.
Defining
how
complex
cell-cell
interactions
become
dysregulated
in
AD
requires
novel
human
cell-based
vitro
platforms
that
could
recapitulate
the
intricate
cytoarchitecture
diversity
brain.
Brain
organoids
(BOs)
are
3D
self-organizing
tissues
partially
resemble
architecture
can
AD-relevant
pathology.
In
this
review,
we
highlight
versatile
applications
different
types
BOs
model
pathogenesis,
including
amyloid-β
tau
aggregation,
neuroinflammation,
myelin
breakdown,
vascular
dysfunction,
other
phenotypes,
as
well
accelerate
therapeutic
development
for
AD.
Alzheimer s & Dementia,
Год журнала:
2021,
Номер
18(5), С. 988 - 1007
Опубликована: Сен. 28, 2021
Abstract
Studies
supporting
a
strong
association
between
tau
deposition
and
neuronal
loss,
neurodegeneration,
cognitive
decline
have
heightened
the
allure
of
tau‐related
mechanisms
as
therapeutic
targets.
In
February
2020,
leading
experts
from
around
world
convened
for
first‐ever
Tau2020
Global
Conference
in
Washington,
DC,
co‐organized
cosponsored
by
Rainwater
Charitable
Foundation,
Alzheimer's
Association,
CurePSP.
Representing
academia,
industry,
government,
philanthropic
sector,
presenters
attendees
discussed
recent
advances
current
directions
research.
The
meeting
provided
unique
opportunity
to
move
research
forward
fostering
global
partnerships
among
other
stakeholders
providing
support
new
drug
discovery
programs,
groundbreaking
research,
emerging
researchers.
also
an
present
critical
research‐advancing
tools
insights
that
are
now
rapidly
accelerating
pace
Journal of Medicinal Chemistry,
Год журнала:
2022,
Номер
65(13), С. 8550 - 8595
Опубликована: Июнь 27, 2022
A
person
suspected
of
having
Alzheimer's
disease
(AD)
is
clinically
diagnosed
for
the
presence
principal
biomarkers,
especially
misfolded
amyloid-beta
(Aβ)
and
tau
proteins
in
brain
regions.
Existing
radiotracer
diagnostic
tools,
such
as
PET
imaging,
are
expensive
have
limited
availability
primary
patient
screening
pre-clinical
animal
studies.
To
change
status
quo,
small-molecular
near-infrared
(NIR)
probes
been
rapidly
developed,
which
may
serve
an
inexpensive,
handy
imaging
tool
to
comprehend
dynamics
pathogenic
progression
AD
assess
therapeutic
efficacy
vivo.
This
Perspective
summarizes
biochemistry
Aβ
then
focuses
on
structurally
diverse
NIR
with
coverages
their
spectroscopic
properties,
binding
affinity
toward
species,
theranostic
effectiveness.
With
summarized
information
perspective
discussions,
we
hope
that
this
paper
a
guiding
designing
novel
vivo
fluoroprobes
capabilities
future.
The
protein
tau
associates
with
microtubules
to
maintain
neuronal
health.
Posttranslational
modifications
of
interfere
this
binding,
leading
aggregation
in
neurodegenerative
disorders.
Here,
we
use
solid-state
nuclear
magnetic
resonance
(NMR)
investigate
the
structure
microtubule-binding
domain
tau.
Wild-type
that
contains
four
repeats
and
a
pseudorepeat
R′
is
studied.
Complexed
taxol-stabilized
microtubules,
immobilized
residues
exhibit
well-resolved
two-dimensional
spectra
can
be
assigned
amino-terminal
region
R4
domain.
When
coassembles
tubulin
form
unstable
signals
remain,
whereas
disappear,
indicating
remains
immobilized,
becomes
more
mobile.
Therefore,
outcompetes
other
associate
microtubules.
These
NMR
data,
together
previous
cryo–electron
microscopy
densities,
indicate
an
extended
conformation
for
microtubule-bound
R′.
largest
number
charged
among
all
repeats,
suggesting
charge-charge
interaction
drives
tau-microtubule
association.
Nature Communications,
Год журнала:
2023,
Номер
14(1)
Опубликована: Май 26, 2023
Accumulation
of
filamentous
aggregates
tau
protein
in
the
brain
is
a
pathological
hallmark
Alzheimer's
disease
(AD)
and
many
other
neurodegenerative
tauopathies.
The
filaments
adopt
disease-specific
cross-β
amyloid
conformations
that
self-propagate
are
implicated
neuronal
loss.
Development
molecular
diagnostics
therapeutics
critical
importance.
However,
mechanisms
small
molecule
binding
to
core
poorly
understood.
We
used
cryo-electron
microscopy
determine
2.7
Å
structure
AD
patient-derived
paired-helical
bound
PET
ligand
GTP-1.
compound
stoichiometrically
at
single
site
along
an
exposed
cleft
each
protofilament
stacked
arrangement
matching
fibril
symmetry.
Multiscale
modeling
reveals
pi-pi
aromatic
interactions
pair
favorably
with
molecule-protein
contacts,
supporting
high
specificity
affinity
for
conformation.
This
mode
offers
insight
into
designing
compounds
target
different
folds
found
across
diseases.
Trends in Molecular Medicine,
Год журнала:
2023,
Номер
29(8), С. 659 - 672
Опубликована: Июнь 22, 2023
Progression
of
Alzheimer's
disease
(AD)
entails
deterioration
or
aberrant
function
multiple
brain
cell
types,
eventually
leading
to
neurodegeneration
and
cognitive
decline.
Defining
how
complex
cell-cell
interactions
become
dysregulated
in
AD
requires
novel
human
cell-based
vitro
platforms
that
could
recapitulate
the
intricate
cytoarchitecture
diversity
brain.
Brain
organoids
(BOs)
are
3D
self-organizing
tissues
partially
resemble
architecture
can
AD-relevant
pathology.
In
this
review,
we
highlight
versatile
applications
different
types
BOs
model
pathogenesis,
including
amyloid-β
tau
aggregation,
neuroinflammation,
myelin
breakdown,
vascular
dysfunction,
other
phenotypes,
as
well
accelerate
therapeutic
development
for
AD.
