Frontiers in Neuroscience,
Год журнала:
2017,
Номер
11
Опубликована: Июнь 2, 2017
The
"therapeutic
chelation"
approach
to
treating
Alzheimer's
disease
(AD)
evolved
from
the
metals
hypothesis,
with
premise
that
small
molecules
can
be
designed
prevent
transition
metal-induced
amyloid
deposition
and
oxidative
stress
within
AD
brain.
Over
more
than
20
years,
countless
Alzheimer s & Dementia,
Год журнала:
2024,
Номер
unknown
Опубликована: Ноя. 13, 2024
Abstract
INTRODUCTION
Alzheimer's
disease
(AD)
is
the
most
prevalent
neurodegenerative
disease,
yet
our
comprehension
predominantly
relies
on
studies
within
non‐Hispanic
White
(NHW)
populations.
Here
we
provide
an
extensive
survey
of
proteomic
landscape
AD
across
diverse
racial/ethnic
groups.
METHODS
Two
cortical
regions,
from
multiple
centers,
were
harmonized
by
uniform
neuropathological
diagnosis.
Among
998
unique
donors,
273
donors
self‐identified
as
African
American,
229
Latino
and
434
NHW.
RESULTS
While
amyloid
precursor
protein
microtubule‐associated
tau
demonstrated
higher
abundance
in
brains,
no
significant
race‐related
differences
observed.
Further
proteome‐wide
focused
analyses
(specific
beta
[Aβ]
species
domains)
supported
absence
racial
these
pathologies
brain
proteome.
DISCUSSION
Our
findings
indicate
that
risk
clinical
presentation
are
not
underpinned
dramatically
divergent
patterns
proteome,
suggesting
other
determinants
account
for
disparities.
Highlights
We
present
a
large‐scale
proteome
(∼10,000
proteins)
DLPFC
(998)
STG
(244)
cases.
About
50%
samples
racially
ethnically
donors.
Key
proteins
(amyloid
tau)
correlated
with
CERAD
Braak
stages.
No
levels
observed
brains.
AD‐associated
changes
showed
strong
correlation
between
proteomes
American
individuals.
This
dataset
advances
understanding
ethnoracial‐specific
pathways
potential
therapies.
Molecular & Cellular Proteomics,
Год журнала:
2024,
Номер
23(2), С. 100721 - 100721
Опубликована: Янв. 20, 2024
Alzheimer's
disease
(AD)
is
characterised
by
several
neuropathological
changes,
mainly
extracellular
amyloid
aggregates
(plaques),
intraneuronal
inclusions
of
phosphorylated
tau
(tangles),
as
well
neuronal
and
synaptic
degeneration,
accompanied
tissue
reactions
to
these
processes
(astrocytosis
microglial
activation)
that
precede
network
disturbances
in
the
symptomatic
phase
disease.
A
number
biomarkers
for
brain
changes
have
been
developed,
using
immunoassays.
In
this
review,
we
discuss
how
targeted
mass
spectrometry
(TMS)
can
be
used
validate
further
characterize
classes
reflecting
different
AD
pathologies,
such
tau-
amyloid-beta
dysfunction,
lysosomal
dysregulation,
axonal
damage,
prospect
TMS
measure
proteins
clinical
research
diagnosis.
advantages
disadvantages
relation
immunoassays
are
discussed,
complementary
aspects
technologies
discussed.
Despite
the
importance
of
protein
glycosylation
to
brain
health,
current
knowledge
glycosylated
proteoforms
or
glycoforms
in
human
and
their
alterations
Alzheimer’s
disease
(AD)
is
limited.
Here,
we
report
a
proteome-wide
glycoform
profiling
study
AD
control
brains
using
intact
glycopeptide-based
quantitative
glycoproteomics
coupled
with
systems
biology.
Our
identified
more
than
10,000
N-glycoforms
from
nearly
1200
glycoproteins
uncovered
signatures
altered
glycan
modifications,
including
reduced
sialylation
N-glycan
branching
elongation
as
well
elevated
mannosylation
truncation
AD.
Network
analyses
revealed
higher-order
organization
glycoproteome
into
networks
coregulated
glycans
discovered
modules
associated
clinical
phenotype,
amyloid-β
accumulation,
tau
pathology.
findings
provide
valuable
insights
pathogenesis
rich
resource
changes
pave
way
forward
for
developing
glycosylation-based
therapies
biomarkers
Dystrophic
neurites
(also
termed
axonal
spheroids)
are
found
around
amyloid
deposits
in
Alzheimer's
disease
(AD),
where
they
impair
electrical
conduction,
disrupt
neural
circuits
and
correlate
with
AD
severity.
Despite
their
importance,
the
mechanisms
underlying
spheroid
formation
remain
incompletely
understood.
To
address
this,
we
developed
a
proximity
labeling
approach
to
uncover
proteome
of
spheroids
human
postmortem
mouse
brains.
Additionally,
established
induced
pluripotent
stem
cell
(iPSC)-derived
model
enabling
mechanistic
investigation
optical
electrophysiology.
These
complementary
approaches
revealed
subcellular
molecular
architecture
identified
abnormalities
key
biological
processes,
including
protein
turnover,
cytoskeleton
dynamics
lipid
transport.
Notably,
PI3K/AKT/mTOR
pathway,
which
regulates
these
was
activated
spheroids.
Furthermore,
phosphorylated
mTOR
levels
correlated
severity
humans.
inhibition
iPSC-derived
neurons
mice
ameliorated
pathology.
Altogether,
our
study
provides
multidisciplinary
toolkit
for
investigating
therapeutic
targets
pathology
neurodegeneration.
Axonal
disease.
In
this
study,
using
proteomics
brain
iPSC
modeling,
authors
link
dysregulated
mTOR,
cytoskeletal
transport
signaling.
Frontiers in Neuroscience,
Год журнала:
2017,
Номер
11
Опубликована: Июнь 2, 2017
The
"therapeutic
chelation"
approach
to
treating
Alzheimer's
disease
(AD)
evolved
from
the
metals
hypothesis,
with
premise
that
small
molecules
can
be
designed
prevent
transition
metal-induced
amyloid
deposition
and
oxidative
stress
within
AD
brain.
Over
more
than
20
years,
countless