Alzheimer s Research & Therapy,
Journal Year:
2023,
Volume and Issue:
15(1)
Published: Dec. 15, 2023
Abstract
Background
Alzheimer’s
disease
(AD)
is
characterized
by
cognitive
dysfunction
and
amyloid
plaques
composed
of
the
amyloid-beta
peptide
(Aβ).
APOE
greatest
genetic
risk
for
AD
with
APOE4
increasing
up
to
~
15-fold
compared
APOE3.
Evidence
suggests
that
levels
lipidation
apoE
protein
could
regulate
progression.
In
glia,
lipidated
via
cholesterol
efflux
from
intracellular
pools,
primarily
ATP-binding
cassette
transporter
A1
(ABCA1).
Therefore,
ABCA1
activity
suggested
be
a
therapeutic
approach
AD.
CS-6253
(CS)
novel
mimetic
was
developed
bind
stabilize
maintain
its
localization
into
plasma
membrane
therefore
promoting
efflux.
The
goal
this
study
determine
whether
CS
modulate
lipidation,
Aβ
pathology,
behavior
in
model
expresses
human
overproduce
Aβ.
Methods
vitro,
APOE3
-glia
or
were
treated
CS.
vivo,
male
female,
E3FAD
(5xFAD
+/−
/
+/+
)
E4FAD
mice
intraperitoneal
injection
at
early
(from
4
8
months
age)
late
ages
10
age).
ApoE
levels,
and,
measured
western
blot
ELISA.
assessed
histochemistry
Learning
memory
tested
Morris
Water
Maze
synaptic
proteins
Western
blot.
Results
treatment
increased
primary
glial
cultures.
young
mice,
soluble
lipid-associated
apoE,
reduced
oAβ
insoluble
as
well
deposition,
improved
levels.
did
not
induce
any
benefits
female
groups
when
started
later
ages.
Conclusions
pathology
only
E3FAD,
cohort
least
pathology.
degree
overproduction
may
impact
ability
targeting
an
effective
therapeutic.
This
ABCA1-stabilizing
works
best
conditions
modest
Acta Neuropathologica Communications,
Journal Year:
2024,
Volume and Issue:
12(1)
Published: Feb. 5, 2024
Deposition
of
amyloid
beta
(Aβ)
into
plaques
is
a
major
hallmark
Alzheimer's
disease
(AD).
Different
precursor
protein
(APP)
mutations
cause
early-onset
AD
by
altering
the
production
or
aggregation
properties
Aβ.
We
recently
identified
Uppsala
APP
mutation
(APPUpp),
which
causes
Aβ
pathology
triple
mechanism:
increased
β-secretase
and
altered
α-secretase
cleavage,
leading
to
formation
unique
conformer
that
rapidly
aggregates
deposits
in
brain.
The
aim
this
study
was
further
explore
effects
APPUpp
transgenic
mouse
model
(tg-UppSwe),
expressing
human
with
together
APPSwe
mutation.
studied
tg-UppSwe
brains
at
different
ages,
using
ELISA
immunohistochemistry.
In
vivo
PET
imaging
three
radioligands
conducted
aged
mice
two
other
models;
tg-ArcSwe
tg-Swe.
Finally,
glial
responses
were
cell
culture
models
brain
tissue,
Tg-UppSwe
displayed
cleavage
suppressed
resulting
AβUpp42
dominated
diffuse
plaque
appearing
from
age
5-6
months.
γ-secretase
not
affected.
Contrary
tg-Swe
mice,
[11C]PiB-PET
negative.
Antibody-based
3D6
ligand
visualized
all
models,
whereas
protofibril
selective
mAb158
did
give
any
signals
mice.
Moreover,
unlike
very
faint
response
pathology.
thus
recapitulates
several
pathological
features
carriers.
presumed
structural
found
affect
their
interaction
anti-Aβ
antibodies
profoundly
modify
Aβ-mediated
response,
may
be
important
aspects
consider
for
development
therapies.
International Journal of Molecular Sciences,
Journal Year:
2024,
Volume and Issue:
25(19), P. 10797 - 10797
Published: Oct. 8, 2024
Alzheimer's
disease
(AD)
is
the
most
common
type
of
dementia
worldwide.
The
etiopathogenesis
this
remains
unknown.
Currently,
several
hypotheses
attempt
to
explain
its
cause,
with
well-studied
being
cholinergic,
beta-amyloid
(Aβ),
and
Tau
hypotheses.
Lately,
there
has
been
increasing
interest
in
role
immunological
factors
other
proteins
such
as
alpha-synuclein
(α-syn)
transactive
response
DNA-binding
protein
43
kDa
(TDP-43).
Recent
studies
emphasize
tunneling
nanotubes
(TNTs)
spread
pathological
within
brains
AD
patients.
TNTs
are
small
membrane
protrusions
composed
F-actin
that
connect
non-adjacent
cells.
Conditions
pathogen
infections,
oxidative
stress,
inflammation,
misfolded
accumulation
lead
formation
TNTs.
These
structures
have
shown
transport
Aβ,
Tau,
α-syn,
TDP-43
between
central
nervous
system
(CNS)
cells,
confirmed
by
vitro
studies.
Besides
their
spreading
pathology,
may
also
protective
functions.
Neurons
burdened
α-syn
can
transfer
aggregates
glial
cells
receive
healthy
mitochondria,
thereby
reducing
cellular
stress
associated
accumulation.
Current
treatments
focus
on
alleviating
symptoms,
clinical
trials
Aβ-lowering
drugs
proven
ineffective.
Therefore,
intensifying
research
could
bring
scientists
closer
a
better
understanding
development
effective
therapies.
Cellular and Molecular Neurobiology,
Journal Year:
2023,
Volume and Issue:
43(6), P. 3023 - 3035
Published: May 2, 2023
Abstract
Growing
evidence
indicates
that
the
pathological
alpha-synuclein
(α-syn)
aggregation
in
Parkinson’s
disease
(PD)
and
dementia
with
Lewy
bodies
(DLB)
starts
at
synapses.
Physiologic
α-syn
is
involved
regulating
neurotransmitter
release
by
binding
to
SNARE
complex
protein
VAMP-2
on
synaptic
vesicles.
However,
which
way
formation
affected
pathology
remains
unclear.
In
this
study,
primary
cortical
neurons
were
exposed
either
monomers
or
preformed
fibrils
(PFFs)
for
different
time
points
effect
distribution
was
analyzed
a
novel
proximity
ligation
assay
(PLA).
Short-term
exposure
PFFs
24
h
increased
co-localization
of
syntaxin-1,
but
reduced
SNAP-25
indicating
direct
added
distribution.
Long-term
7
d
co-localization,
although
there
only
modest
induction
ser129
phosphorylated
(pS129)
α-syn.
Similarly,
extracellular
vesicles
collected
from
astrocytes
treated
influenced
despite
low
levels
pS129
being
formed.
Taken
together,
our
results
demonstrate
proteoforms
have
potential
alter
proteins
synapse.
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