Nature Communications,
Journal Year:
2024,
Volume and Issue:
15(1)
Published: June 20, 2024
Abstract
To
uncover
molecular
changes
underlying
blood-brain-barrier
dysfunction
in
Alzheimer’s
disease,
we
performed
single
nucleus
RNA
sequencing
24
disease
and
control
brains
focused
on
vascular
astrocyte
clusters
as
main
cell
types
of
gliovascular-unit.
The
majority
the
transcriptional
were
pericytes.
Of
targets
predicted
to
interact
with
astrocytic
ligands,
SMAD3
,
upregulated
pericytes,
has
highest
number
ligands
including
VEGFA
downregulated
astrocytes.
We
validated
these
findings
external
datasets
comprising
4,730
pericyte
150,664
nuclei.
Blood
levels
are
associated
disease-related
neuroimaging
outcomes.
determined
inverse
relationships
between
pericytic
human
iPSC
zebrafish
models.
Here,
detect
vast
transcriptome
at
gliovascular-unit,
prioritize
perturbed
-astrocytic
interactions,
validate
cross-species
models
provide
a
mechanism
disintegrity
disease.
Cell,
Journal Year:
2023,
Volume and Issue:
186(20), P. 4386 - 4403.e29
Published: Sept. 1, 2023
Altered
microglial
states
affect
neuroinflammation,
neurodegeneration,
and
disease
but
remain
poorly
understood.
Here,
we
report
194,000
single-nucleus
transcriptomes
epigenomes
across
443
human
subjects
diverse
Alzheimer's
(AD)
pathological
phenotypes.
We
annotate
12
transcriptional
states,
including
AD-dysregulated
homeostatic,
inflammatory,
lipid-processing
states.
identify
1,542
AD-differentially-expressed
genes,
both
microglia-state-specific
disease-stage-specific
alterations.
By
integrating
epigenomic,
transcriptomic,
motif
information,
infer
upstream
regulators
of
cell
gene-regulatory
networks,
enhancer-gene
links,
transcription-factor-driven
state
transitions.
demonstrate
that
ectopic
expression
our
predicted
homeostatic-state
activators
induces
homeostatic
features
in
iPSC-derived
microglia-like
cells,
while
inhibiting
inflammation
can
block
inflammatory
progression.
Lastly,
pinpoint
the
AD-risk
genes
differential
their
during
AD
Overall,
provide
insights
underlying
state-specific
AD-stage-specific
alterations
at
unprecedented
resolution.
Cell,
Journal Year:
2023,
Volume and Issue:
186(20), P. 4422 - 4437.e21
Published: Sept. 1, 2023
Recent
work
has
identified
dozens
of
non-coding
loci
for
Alzheimer's
disease
(AD)
risk,
but
their
mechanisms
and
AD
transcriptional
regulatory
circuitry
are
poorly
understood.
Here,
we
profile
epigenomic
transcriptomic
landscapes
850,000
nuclei
from
prefrontal
cortexes
92
individuals
with
without
to
build
a
map
the
brain
regulome,
including
profiles,
regulators,
co-accessibility
modules,
peak-to-gene
links
in
cell-type-specific
manner.
We
develop
methods
multimodal
integration
detecting
modules
using
linking.
show
risk
enriched
microglial
enhancers
specific
TFs
SPI1,
ELF2,
RUNX1.
detect
9,628
ATAC-QTL
loci,
which
integrate
alongside
prioritize
variant
circuits.
report
differential
accessibility
late
glia
early
neurons.
Strikingly,
late-stage
brains
global
epigenome
dysregulation
indicative
erosion
cell
identity
loss.
Cell,
Journal Year:
2023,
Volume and Issue:
186(20), P. 4404 - 4421.e20
Published: Sept. 1, 2023
Persistent
DNA
double-strand
breaks
(DSBs)
in
neurons
are
an
early
pathological
hallmark
of
neurodegenerative
diseases
including
Alzheimer's
disease
(AD),
with
the
potential
to
disrupt
genome
integrity.
We
used
single-nucleus
RNA-seq
human
postmortem
prefrontal
cortex
samples
and
found
that
excitatory
AD
were
enriched
for
somatic
mosaic
gene
fusions.
Gene
fusions
particularly
damage
repair
senescence
signatures.
In
addition,
structural
variations
burdened
DSBs
CK-p25
mouse
model
neurodegeneration.
Neurons
also
had
elevated
levels
cohesin
along
progressive
multiscale
disruption
3D
organization
aligned
transcriptional
changes
synaptic,
neuronal
development,
histone
genes.
Overall,
this
study
demonstrates
stability
by
as
steps
progression
diseases.
Nature,
Journal Year:
2024,
Volume and Issue:
632(8026), P. 858 - 868
Published: July 24, 2024
Abstract
Alzheimer’s
disease
is
the
leading
cause
of
dementia
worldwide,
but
cellular
pathways
that
underlie
its
pathological
progression
across
brain
regions
remain
poorly
understood
1–3
.
Here
we
report
a
single-cell
transcriptomic
atlas
six
different
in
aged
human
brain,
covering
1.3
million
cells
from
283
post-mortem
samples
48
individuals
with
and
without
disease.
We
identify
76
cell
types,
including
region-specific
subtypes
astrocytes
excitatory
neurons
an
inhibitory
interneuron
population
unique
to
thalamus
distinct
canonical
subclasses.
vulnerable
populations
are
depleted
specific
disease,
provide
evidence
Reelin
signalling
pathway
involved
modulating
vulnerability
these
neurons.
develop
scalable
method
for
discovering
gene
modules,
which
use
cell-type-specific
modules
altered
annotate
differences
associated
diverse
variables.
astrocyte
program
cognitive
resilience
pathology,
tying
choline
metabolism
polyamine
biosynthesis
preserved
function
late
life.
Together,
our
study
develops
regional
ageing
provides
insights
into
vulnerability,
response
pathology.
Nature Neuroscience,
Journal Year:
2024,
Volume and Issue:
unknown
Published: Oct. 14, 2024
Alzheimer's
disease
(AD)
is
the
leading
cause
of
dementia
in
older
adults.
Although
AD
progression
characterized
by
stereotyped
accumulation
proteinopathies,
affected
cellular
populations
remain
understudied.
Here
we
use
multiomics,
spatial
genomics
and
reference
atlases
from
BRAIN
Initiative
to
study
middle
temporal
gyrus
cell
types
84
donors
with
varying
pathologies.
This
cohort
includes
33
male
51
female
donors,
an
average
age
at
time
death
88
years.
We
used
quantitative
neuropathology
place
along
a
pseudoprogression
score.
Pseudoprogression
analysis
revealed
two
phases:
early
phase
slow
increase
pathology,
presence
inflammatory
microglia,
reactive
astrocytes,
loss
somatostatin
Protein & Cell,
Journal Year:
2024,
Volume and Issue:
unknown
Published: May 11, 2024
Abstract
Alzheimer’s
disease
(AD),
the
leading
cause
of
dementia,
is
characterized
by
accumulation
amyloid
plaques
and
neurofibrillary
tangles
in
brain.
This
condition
casts
a
significant
shadow
on
global
health
due
to
its
complex
multifactorial
nature.
In
addition
genetic
predispositions,
development
AD
influenced
myriad
risk
factors,
including
aging,
systemic
inflammation,
chronic
conditions,
lifestyle,
environmental
exposures.
Recent
advancements
understanding
pathophysiology
are
paving
way
for
enhanced
diagnostic
techniques,
improved
assessment,
potentially
effective
prevention
strategies.
These
discoveries
crucial
quest
unravel
complexities
AD,
offering
beacon
hope
management
treatment
options
millions
affected
this
debilitating
disease.
