Annual Review of Pathology Mechanisms of Disease,
Год журнала:
2014,
Номер
10(1), С. 291 - 319
Опубликована: Ноя. 11, 2014
Alzheimer's
disease/senile
dementia
of
the
Alzheimer
type
(AD/SDAT)
is
most
common
neuropathologic
substrate
dementia.
It
characterized
by
synapse
loss
(predominantly
within
neocortex)
as
well
deposition
certain
distinctive
lesions
(the
result
protein
misfolding)
throughout
brain.
The
latter
include
senile
plaques,
composed
mainly
an
amyloid
(Aβ)
core
and
a
neuritic
component;
neurofibrillary
tangles,
predominantly
hyperphosphorylated
tau;
cerebral
angiopathy,
microangiopathy
affecting
both
cortical
capillaries
arterioles
resulting
from
Aβ
their
walls
or
(in
case
capillaries)
immediately
adjacent
brain
parenchyma.
In
this
article,
I
discuss
hypothesized
role
these
play
in
causing
dysfunction,
CSF
neuroimaging
biomarkers
(for
dementia)
that
are
especially
relevant
immunotherapeutic
approaches
being
developed
to
remove
addition,
address
neuropathology
characterizing
sequelae
new
AD/SDAT
therapies
helping
validate
disease.
Comorbidity
various
types
cerebrovascular
disease
major
theme
research,
cognitive
impairment
develops
oldest
old,
who
vulnerable
ischemic
hemorrhagic
lesions.
Experimental & Molecular Medicine,
Год журнала:
2015,
Номер
47(3), С. e147 - e147
Опубликована: Март 13, 2015
Mammalian
cells
remove
misfolded
proteins
using
various
proteolytic
systems,
including
the
ubiquitin
(Ub)-proteasome
system
(UPS),
chaperone
mediated
autophagy
(CMA)
and
macroautophagy.
The
majority
of
are
degraded
by
UPS,
in
which
Ub-conjugated
substrates
deubiquitinated,
unfolded
cleaved
into
small
peptides
when
passing
through
narrow
chamber
proteasome.
that
expose
a
specific
degradation
signal,
KFERQ
sequence
motif,
can
be
delivered
to
lysosomes
via
CMA.
Aggregation-prone
resistant
both
UPS
CMA
macroautophagy,
cargoes
segregated
autophagosomes
before
lysosomal
hydrolases.
Although
most
aggregated
human
proteome
cellular
protein
quality
control,
some
native
mutant
prone
aggregation
β-sheet-enriched
oligomers
all
known
pathways
thus
grow
inclusion
bodies
or
extracellular
plaques.
accumulation
protease-resistant
is
common
mechanism
underlying
misfolding
disorders,
neurodegenerative
diseases
such
as
Huntington's
disease
(HD),
Alzheimer's
(AD),
Parkinson's
(PD),
prion
Amyotrophic
Lateral
Sclerosis
(ALS).
In
this
review,
we
provide
an
overview
neurons,
with
emphasis
on
discuss
role
control
pathogenic
diseases.
Additionally,
examine
existing
putative
therapeutic
strategies
efficiently
cytotoxic
from
degenerating
neurons.
Frontiers in Neurology,
Год журнала:
2013,
Номер
4
Опубликована: Янв. 1, 2013
Fibrillar
deposits
of
highly
phosphorylated
tau
are
a
key
pathological
feature
several
neurodegenerative
tauopathies
including
Alzheimer's
disease
(AD)
and
some
frontotemporal
dementias.
Increasing
evidence
suggests
that
the
presence
these
end-stage
neurofibrillary
lesions
do
not
cause
neuronal
loss,
but
rather
alterations
to
soluble
proteins
induce
neurodegeneration.
In
particular,
aberrant
phosphorylation
is
acknowledged
be
process,
influencing
structure,
distribution,
function
in
neurons.
Although
typically
described
as
cytosolic
protein
associates
with
microtubules
regulates
axonal
transport,
additional
functions
have
recently
been
demonstrated,
roles
DNA
stabilization,
synaptic
function.
Most
recently,
studies
examining
trans-synaptic
spread
pathology
models
suggested
potential
role
for
extracellular
cell
signaling
pathways
intrinsic
Here
we
review
showing
plays
tauopathies.
We
also
comment
on
tractability
altering
phosphorylation-dependent
therapeutic
intervention
AD
related
disorders.
Nature Communications,
Год журнала:
2017,
Номер
8(1)
Опубликована: Май 11, 2017
Abstract
Tau
is
implicated
in
more
than
20
neurodegenerative
diseases,
including
Alzheimer’s
disease.
Under
pathological
conditions,
dissociates
from
axonal
microtubules
and
missorts
to
pre-
postsynaptic
terminals.
Patients
suffer
early
synaptic
dysfunction
prior
aggregate
formation,
but
the
underlying
mechanism
unclear.
Here
we
show
that
pathogenic
binds
vesicles
via
its
N-terminal
domain
interferes
with
presynaptic
functions,
vesicle
mobility
release
rate,
lowering
neurotransmission
fly
rat
neurons.
Pathological
mutants
lacking
binding
still
localize
compartment
do
not
impair
function
Moreover,
an
exogenously
applied
membrane-permeable
peptide
competes
for
Tau-vesicle
suppresses
Tau-induced
toxicity
Our
work
uncovers
a
role
of
may
be
part
pathology
various
Tauopathies
could
exploited
therapeutically.
