Cell Reports,
Год журнала:
2021,
Номер
34(1), С. 108572 - 108572
Опубликована: Янв. 1, 2021
Alzheimer's
disease
(AD)
risk
gene
ApoE4
perturbs
brain
lipid
homeostasis
and
energy
transduction.
However,
the
cell-type-specific
mechanism
of
in
modulating
metabolism
is
unclear.
Here,
we
describe
a
detrimental
role
regulating
fatty
acid
(FA)
across
neuron
astrocyte
tandem
with
their
distinctive
mitochondrial
phenotypes.
disrupts
neuronal
function
by
decreasing
FA
sequestering
droplets
(LDs).
FAs
LDs
are
exported
internalized
astrocytes,
diminishing
transport
efficiency.
Further,
lowers
oxidation
leads
to
accumulation
both
hippocampus.
Importantly,
diminished
capacity
astrocytes
eliminating
lipids
degrading
accounts
for
compromised
metabolic
synaptic
support
neurons.
Collectively,
our
findings
reveal
disruption
bioenergetic
that
could
underlie
accelerated
dysregulation
deficits
increased
AD
carriers.
Physiological Reviews,
Год журнала:
2018,
Номер
99(1), С. 21 - 78
Опубликована: Окт. 3, 2018
The
blood-brain
barrier
(BBB)
prevents
neurotoxic
plasma
components,
blood
cells,
and
pathogens
from
entering
the
brain.
At
same
time,
BBB
regulates
transport
of
molecules
into
out
central
nervous
system
(CNS),
which
maintains
tightly
controlled
chemical
composition
neuronal
milieu
that
is
required
for
proper
functioning.
In
this
review,
we
first
examine
molecular
cellular
mechanisms
underlying
establishment
BBB.
Then,
focus
on
physiology,
endothelial
pericyte
transporters,
perivascular
paravascular
transport.
Next,
discuss
rare
human
monogenic
neurological
disorders
with
primary
genetic
defect
in
BBB-associated
cells
demonstrating
link
between
breakdown
neurodegeneration.
review
effects
genes
inheritance
and/or
increased
susceptibility
Alzheimer's
disease
(AD),
Parkinson's
(PD),
Huntington's
disease,
amyotrophic
lateral
sclerosis
(ALS)
relation
to
other
pathologies
deficits.
We
next
how
dysfunction
relates
deficits
majority
sporadic
AD,
PD,
ALS
cases,
multiple
sclerosis,
neurodegenerative
disorders,
acute
CNS
such
as
stroke,
traumatic
brain
injury,
spinal
cord
epilepsy.
Lastly,
BBB-based
therapeutic
opportunities.
conclude
lessons
learned
future
directions,
emphasis
technological
advances
investigate
functions
living
brain,
at
level,
address
key
unanswered
questions.
Converging
paradigms
in
neurodegeneration
Parkinson's
disease
and
Alzheimer's
are
progressive
neurodegenerative
diseases
with
increasing
prevalence
our
aging
populations.
Recent
evidence
suggests
that
some
of
the
molecular
mechanisms
involved
pathology
these
have
similarities
to
those
observed
infectious
prion
such
as
bovine
spongiform
encephalopathy
(mad
cow
disease).
Goedert
reviews
how
spread
a
variety
pathological
protein
aggregates
is
disease.
Science
,
this
issue
p.
10.1126/science.1255555
Journal of Molecular Medicine,
Год журнала:
2016,
Номер
94(7), С. 739 - 746
Опубликована: Июнь 9, 2016
Apolipoprotein
(apo)
E
was
initially
described
as
a
lipid
transport
protein
and
major
ligand
for
low
density
lipoprotein
(LDL)
receptors
with
role
in
cholesterol
metabolism
cardiovascular
disease.
It
has
since
emerged
risk
factor
(causative
gene)
Alzheimer's
disease
other
neurodegenerative
disorders.
Detailed
understanding
of
the
structural
features
three
isoforms
(apoE2,
apoE3,
apoE4),
which
differ
by
only
single
amino
acid
interchange,
elucidated
their
unique
functions.
ApoE2
apoE4
increase
heart
disease:
apoE2
increases
atherogenic
levels
(it
binds
poorly
to
LDL
receptors),
preferentially
triglyceride-rich,
very
lipoproteins,
leading
downregulation
receptors).
ApoE4
also
diseases,
decreases
age
onset,
or
alters
progression.
likely
causes
neurodegeneration
secondary
its
abnormal
structure,
caused
an
interaction
between
carboxyl-
amino-terminal
domains,
called
domain
interaction.
When
neurons
are
stressed
injured,
they
synthesize
apoE
redistribute
neuronal
repair
remodeling.
However,
because
altered
undergoes
neuron-specific
proteolysis,
generating
neurotoxic
fragments
(12–29
kDa)
that
escape
secretory
pathway
cause
mitochondrial
dysfunction
cytoskeletal
alterations,
including
tau
phosphorylation.
ApoE4-associated
pathology
can
be
prevented
small-molecule
structure
correctors
block
converting
molecule
resembles
apoE3
both
structurally
functionally.
Structure
potential
therapeutic
approach
reduce
neurological
Alzheimer s & Dementia,
Год журнала:
2018,
Номер
14(9), С. 1171 - 1183
Опубликована: Июнь 12, 2018
Abstract
Introduction
Precision
medicine
methodologies
and
approaches
have
advanced
our
understanding
of
the
clinical
presentation,
development,
progression,
management
Alzheimer's
disease
(AD)
dementia.
However,
sex
gender
not
yet
been
adequately
integrated
into
many
these
approaches.
Methods
The
Society
for
Women's
Health
Research
Interdisciplinary
Network
on
AD,
comprised
an
expert
panel
scientists
clinicians,
reviewed
ongoing
published
research
related
to
differences
in
AD.
Results
current
review
is
a
result
this
Network's
efforts
aims
to:
(1)
highlight
state‐of‐the‐science
AD
field
differences;
(2)
address
knowledge
gaps
assessing
(3)
discuss
12
priority
areas
that
merit
further
research.
Discussion
exclusion
has
impeded
faster
advancement
detection,
treatment,
care
across
spectrum.
Greater
attention
will
improve
outcomes
both
sexes.
