Journal of Neurochemistry,
Journal Year:
2021,
Volume and Issue:
160(4), P. 434 - 453
Published: Nov. 12, 2021
Although
controversial,
the
amyloid
cascade
hypothesis
remains
central
to
Alzheimer's
disease
(AD)
field
and
posits
amyloid-beta
(Aβ)
as
factor
initiating
onset.
In
recent
years,
there
has
been
an
increase
in
emphasis
on
studying
role
of
low
molecular
weight
aggregates,
such
oligomers,
which
are
suggested
be
more
neurotoxic
than
fibrillary
Aβ.
Other
Aβ
isoforms,
truncated
Aβ,
have
also
implicated
disease.
However,
developing
a
clear
understanding
AD
pathogenesis
hampered
by
complexity
biochemistry
vitro
vivo.
This
review
explores
factors
contributing
lack
consistency
experimental
approaches
taken
model
aggregation
toxicity
provides
overview
different
techniques
available
analyse
electron
atomic
force
microscopy,
nuclear
magnetic
resonance
spectroscopy,
dye-based
assays,
size
exclusion
chromatography,
mass
spectrometry
SDS-PAGE.
The
how
types
can
influence
toxicity,
leading
variation
outcomes,
further
highlighting
need
for
standardisation
preparations
methods
used
current
research.
Angewandte Chemie International Edition,
Journal Year:
2020,
Volume and Issue:
60(6), P. 3016 - 3021
Published: Oct. 23, 2020
Abstract
Amyloid‐β
peptides
(Aβ)
assemble
into
both
rigid
amyloid
fibrils
and
metastable
oligomers
termed
AβO
or
protofibrils.
In
Alzheimer's
disease,
Aβ
constitute
the
core
of
senile
plaques,
but
protofibrils
may
represent
main
toxic
species.
accumulate
at
exterior
yet
protofibril–fibril
interplay
is
not
well
understood.
Applying
chemical
kinetics
atomic
force
microscopy
to
assembly
lysozyme,
are
observed
bind
lateral
surfaces
fibrils.
When
utilizing
variants
with
different
critical
oligomer
concentrations,
interaction
inhibits
autocatalytic
proliferation
by
secondary
nucleation
on
fibril
surface.
Thus,
antagonize
their
replacement
competing
for
monomers
blocking
sites.
The
protofibril—fibril
governs
temporal
evolution
potential
exert
specific
activities.
Nano Letters,
Journal Year:
2023,
Volume and Issue:
23(13), P. 6259 - 6268
Published: May 4, 2023
Amyloid-β
(Aβ)
aggregation
intermediates,
including
oligomers
and
protofibrils
(PFs),
have
attracted
attention
as
neurotoxic
aggregates
in
Alzheimer's
disease.
However,
due
to
the
complexity
of
pathway,
structural
dynamics
intermediates
how
drugs
act
on
them
not
been
clarified.
Here
we
used
high-speed
atomic
force
microscopy
observe
Aβ42
PF
at
single-molecule
level
effect
lecanemab,
an
anti-Aβ
antibody
with
positive
results
from
Phase
3
Clarity
AD.
was
found
be
a
curved
nodal
structure
stable
binding
angle
between
individual
nodes.
also
dynamic
that
associates
other
molecules
undergoes
intramolecular
cleavage.
Lecanemab
remained
PFs
globular
oligomers,
inhibiting
formation
large
aggregates.
These
provide
direct
evidence
for
mechanism
by
which
interfere
Aβ
process.
Molecular Pharmacology,
Journal Year:
2023,
Volume and Issue:
105(1), P. 1 - 13
Published: Oct. 31, 2023
Alzheimer's
disease
(AD)
is
a
neurodegenerative
disorder
characterized
by
amyloid-β
(Aβ)
protein
accumulation
in
the
brain.
Passive
immunotherapies
using
monoclonal
antibodies
for
targeting
Aβ
have
shown
promise
AD
treatment.
Indeed,
recent
US
Food
and
Drug
Administration
approval
of
aducanumab
lecanemab,
alongside
positive
donanemab
Phase
III
results
demonstrated
clinical
efficacy
after
decades
failed
trials
AD.
However,
pharmacological
basis
distinguishing
clinically
effective
from
ineffective
therapies
remains
unclear,
impeding
development
potent
therapeutics.
This
study
aimed
to
provide
quantitative
perspective
effectively
with
antibodies.
We
first
reviewed
contradicting
associated
amyloid
hypothesis
immunotherapy.
Subsequently,
we
developed
systems
pharmacology
(QSP)
model
that
describes
non-linear
progression
pathology
pharmacologic
actions
Aβ-targeting
Using
QSP
model,
analyzed
various
scenarios
passive
immunotherapy
The
revealed
binding
exclusively
monomer
has
minimal
effect
on
aggregation
plaque
reduction,
making
antibody
affinity
toward
unwanted,
as
it
could
become
distractive
mechanism
reduction.
Neither
early
intervention,
high
brain
penetration,
nor
increased
dose
yield
significant
improvement
solely
monomers.
Antibodies
bind
all
species
but
lack
effector
function
exhibited
moderate
effects
Our
highlights
importance
aggregate
incorporating
functions
efficient
guiding
more
this
devastating
disease.
SIGNIFICANCE
STATEMENT
Despite
previous
unsuccessful
attempts
spanning
several
decades,
utilizing
amyloid-beta
two
FDA
approvals.
differentiates
ones
elusive.
offers
perspective,
emphasizing
significance
selectively
specific
functions.
sheds
light
International Journal of Molecular Sciences,
Journal Year:
2020,
Volume and Issue:
21(6), P. 1992 - 1992
Published: March 14, 2020
Cerebral
amyloid
angiopathy
(CAA)
is
a
cerebrovascular
disease
directly
implicated
in
Alzheimer’s
(AD)
pathogenesis
through
amyloid-β
(Aβ)
deposition,
which
may
cause
the
development
and
progression
of
dementia.
Despite
extensive
studies
to
explore
drugs
targeting
Aβ,
clinical
benefits
have
not
been
reported
large
trials
AD
patients
or
presymptomatic
individuals
at
risk
for
AD.
However,
recent
on
CAA
provided
novel
insights
regarding
CAA-
AD-related
pathogenesis.
This
work
has
revealed
potential
therapeutic
targets,
including
Aβ
drainage
pathways,
aggregation,
oxidative
stress,
neuroinflammation.
The
functional
significance
bioactive
molecules
such
as
cilostazol
taxifolin
also
become
increasingly
evident.
Furthermore,
epidemiological
demonstrated
that
serum
levels
soluble
form
triggering
receptor
expressed
myeloid
cells
2
(TREM2)
predictive
biomarker
dementia
incidence.
review
summarizes
advances
research
with
focus
discussing
future
directions
approaches
biomarkers
ACS Chemical Neuroscience,
Journal Year:
2022,
Volume and Issue:
13(10), P. 1467 - 1478
Published: May 4, 2022
Alzheimer's
disease
(AD)
is
a
multifactorial
disease,
and
it
has
become
serious
health
problem
in
the
world.
Senile
plaques
(SPs)
neurofibrillary
tangles
(NFTs)
are
two
main
pathological
characters
of
AD.
SP
mainly
consists
aggregated
β-amyloid
(Aβ),
NFT
formed
by
hyperphosphorylated
tau
protein.
Sleep–wake
disorders
prevalent
AD
patients;
however,
links
mechanisms
sleep–wake
on
pathogenesis
remain
to
be
investigated.
Here,
we
referred
reviewed
some
evidence
demonstrate
relationship
between
On
one
hand,
may
lead
increase
Aβ
production
decrease
clearance,
spreading
pathology,
as
well
oxidative
stress
inflammation.
other
ApoE4
allele,
risk
gene
for
AD,
was
reported
participate
disorders.
Furthermore,
neurotransmitters,
such
acetylcholine,
glutamate,
serotonin,
melatonin,
orexins,
their
receptors
were
suggested
involved
development
We
discussed
possible
therapeutic
strategies
treatment
based
view
sleep
regulation.
In
general,
this
review
explored
different
views
find
novel
targets
diagnosis
therapy
Cells,
Journal Year:
2023,
Volume and Issue:
12(10), P. 1386 - 1386
Published: May 13, 2023
Recent
studies
have
revealed
that
soluble
amyloid-β
oligomers
(AβOs)
play
a
pathogenetic
role
in
Alzheimer’s
disease
(AD).
Indeed,
AβOs
induce
neurotoxic
and
synaptotoxic
effects
are
also
critically
involved
neuroinflammation.
Oxidative
stress
appears
to
be
crucial
event
underlying
these
pathological
of
AβOs.
From
therapeutic
standpoint,
new
drugs
for
AD
designed
remove
or
inhibit
the
formation
currently
being
developed.
However,
it
is
worth
considering
strategies
preventing
AβO
toxicity
itself.
In
particular,
small
molecules
with
toxicity-reducing
activity
potential
as
drug
candidates.
Among
such
molecules,
those
can
enhance
Nrf2
and/or
PPARγ
effectively
toxicity.
this
review,
I
summarize
on
counteract
capable
activating
PPARγ.
discuss
how
interrelated
pathways
mechanisms
by
which
prevent
AβO-induced
neurotoxicity
propose
therapy,
designated
ATR-T,
could
beneficial,
complementary
strategy
prevention
treatment
AD.
The FASEB Journal,
Journal Year:
2025,
Volume and Issue:
39(3)
Published: Feb. 8, 2025
Alzheimer's
disease
(AD)
is
the
most
prevalent
age-related
neurodegenerative
disorder,
mainly
characterized
by
amyloid
β
(Aβ)
accumulation
in
brain.
Numerous
new
agents
are
currently
undergoing
clinical
trials
as
disease-modifying
therapies
(DMTs)
targeting
Aβ.
ALZ-801
a
promising
candidate
DMT
for
AD,
with
phase
3
trial
of
ongoing
specifically
apolipoprotein
E
(APOE)
ε4
homozygous
patients
early-stage
AD.
This
study
aimed
to
examine
effects
on
Aβ
assembly
and
explore
its
toxicological
profile.
Thioflavin
T
(ThT)
assays
two
imaging
modalities-transmission
electron
microscopy
(TEM)
high-speed
atomic
force
(HS-AFM)-were
used
evaluate
ALZ-801's
assembly.
To
assess
effect
Aβ42-induced
cytotoxicity,
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide
(MTT)
lactate
dehydrogenase
(LDH)
were
performed.
ThT
revealed
increased
lag
time
decreased
fluorescence
presence
ALZ-801,
confirming
inhibition
Aβ42
fibril
formation,
confirmed
TEM.
Real-time
observation
using
HS-AFM
that
inhibited
formation
from
low-molecular-weight
(LMW)-Aβ42
seeds.
also
globular
aggregates
LMW-Aβ42
significantly
larger
few
fibrils
noted.
MTT
LDH
indicated
prevented
LMW-Aβ42-induced
cytotoxicity
but
did
not
reduce
induced
high-molecular-weight-Aβ42.
can
inhibit
aggregation
preventing
both
nucleus
elongation,
while
promoting
large
oligomer
cytotoxicity.
These
findings
underscore
potential
an
effective
APOE
