Journal of Neuroscience,
Journal Year:
2011,
Volume and Issue:
31(21), P. 7840 - 7847
Published: May 25, 2011
Stressful
life
experiences
are
likely
etiological
factors
in
sporadic
forms
of
Alzheimer's
disease
(AD).
Many
AD
patients
hypersecrete
glucocorticoids
(GCs),
and
their
GC
levels
correlate
with
the
rate
cognitive
impairment
extent
neuronal
atrophy.
Severity
deficits
correlates
strongly
hyperphosphorylated
cytoskeletal
protein
TAU,
an
essential
mediator
actions
amyloid
β
(Aβ),
another
molecule
a
key
pathogenic
role
AD.
Our
objective
was
to
investigate
sequential
interrelationships
between
these
various
elements,
particular
respect
mechanisms
through
which
stress
might
precipitate
decline.
We
thus
examined
whether
stress,
mediation
GCs,
influences
TAU
hyperphosphorylation,
critical
early
event
cascade
processes
leading
pathology.
Results
from
healthy,
wild-type,
middle-aged
rats
show
that
chronic
induce
abnormal
hyperphosphorylation
hippocampus
prefrontal
cortex
(PFC),
contemporaneous
impairments
hippocampus-
PFC-dependent
behaviors.
Exogenous
potentiated
ability
centrally
infused
Aβ
epitopes
associated
cytoplasmic
accumulation
while
previous
exposure
aggravated
biochemical
behavioral
effects
Aβ-infused
animals.
Thus,
lifetime
stress/GC
may
have
cumulative
impact
on
onset
progress
pathology,
serving
transduce
negative
cognition.
Current Medicinal Chemistry,
Journal Year:
2008,
Volume and Issue:
15(23), P. 2321 - 2328
Published: Sept. 29, 2008
Alzheimer
disease
(AD)
is
the
most
common
cause
of
dementia
in
adults.
The
current
therapy
for
AD
has
only
moderate
efficacy
controlling
symptoms,
and
it
does
not
cure
disease.
Recent
studies
have
suggested
that
abnormal
hyperphosphorylation
tau
brain
plays
a
vital
role
molecular
pathogenesis
neurodegeneration.
This
article
reviews
advances
understanding
protein,
regulation
phosphorylation,
its
neurofibrillary
degeneration.
Furthermore,
several
therapeutic
strategies
treating
on
basis
important
are
described.
These
include
(1)
inhibition
glycogen
synthase
kinase-3β
(GSK-3β),
cyclin-dependent
kinase
5
(cdk5),
other
kinases;
(2)
restoration
PP2A
activity;
(3)
targeting
O-GlcNAcylation.
Development
drugs
these
likely
to
lead
disease-modifying
therapies
AD.
Molecular Neurodegeneration,
Journal Year:
2014,
Volume and Issue:
9(1), P. 48 - 48
Published: Jan. 1, 2014
Alzheimer's
disease
(AD)
is
a
devastating
characterized
by
synaptic
and
neuronal
loss
in
the
elderly.
Compelling
evidence
suggests
that
soluble
amyloid-β
peptide
(Aβ)
oligomers
induce
AD.
Aβ-induced
dysfunction
dependent
on
overstimulation
of
N-methyl-D-aspartate
receptors
(NMDARs)
resulting
aberrant
activation
redox-mediated
events
as
well
elevation
cytoplasmic
Ca2+,
which
turn
triggers
downstream
pathways
involving
phospho-tau
(p-tau),
caspases,
Cdk5/dynamin-related
protein
1
(Drp1),
calcineurin/PP2B,
PP2A,
Gsk-3β,
Fyn,
cofilin,
CaMKII
causes
endocytosis
AMPA
(AMPARs)
NMDARs.
Dysfunction
these
leads
to
mitochondrial
dysfunction,
bioenergetic
compromise
consequent
loss,
impaired
long-term
potentiation
(LTP),
cognitive
decline.
Evidence
also
Aβ
may,
at
least
part,
mediate
causing
an
rise
extrasynaptic
glutamate
levels
inhibiting
uptake
or
triggering
release
from
glial
cells.
Consequent
NMDAR
(eNMDAR)
then
results
via
aforementioned
pathways.
Consistent
with
this
model
toxicity
can
be
partially
ameliorated
antagonists
(such
memantine
NitroMemantine).
PSD-95,
important
scaffolding
regulates
distribution
activity
both
NMDA
receptors,
functionally
disrupted
Aβ.
PSD-95
dysregulation
likely
intermediate
step
pathological
cascade
caused
In
summary,
complicated
process
multiple
pathways,
components
biological
events,
their
underlying
mechanisms,
albeit
yet
incompletely
understood,
may
offer
hope
for
new
therapeutic
avenues.
British Journal of Pharmacology,
Journal Year:
2009,
Volume and Issue:
156(6), P. 885 - 898
Published: March 1, 2009
Glycogen
synthase
kinase
3
(GSK3),
a
constitutively
acting
multi‐functional
serine
threonine
is
involved
in
diverse
physiological
pathways
ranging
from
metabolism,
cell
cycle,
gene
expression,
development
and
oncogenesis
to
neuroprotection.
These
multiple
functions
attributed
GSK3
can
be
explained
by
variety
of
substrates
like
glycogen
synthase,
τ
protein
β
catenin
that
are
phosphorylated
leading
their
inactivation.
has
been
implicated
various
diseases
such
as
diabetes,
inflammation,
cancer,
Alzheimer's
bipolar
disorder.
negatively
regulates
insulin‐mediated
synthesis
glucose
homeostasis,
increased
expression
activity
reported
type
II
diabetics
obese
animal
models.
Consequently,
inhibitors
have
demonstrated
anti‐diabetic
effects
vitro
However,
inhibition
poses
challenge
achieving
selectivity
an
over
with
may
lead
side
toxicity.
The
primary
concern
developing
but
do
not
up‐regulation
oncogenes.
focus
this
review
the
recent
advances
challenges
surrounding
therapeutic
target.
British
Journal
Pharmacology
(2009)
doi:10.1111/j.1476‐5381.2008.00085.x
Physiological Reviews,
Journal Year:
2010,
Volume and Issue:
90(2), P. 465 - 494
Published: April 1, 2010
Alzheimer
disease
is
characterized
by
the
accumulation
of
abnormally
folded
protein
fragments,
i.e.,
amyloid
beta
peptide
(Aβ)
and
tau
that
precipitate
in
plaques
neuronal
tangles,
respectively.
In
this
review
we
discuss
complicated
proteolytic
pathways
are
responsible
for
generation
clearance
these
how
disturbances
interact
provide
a
background
novel
understanding
as
multifactorial
disorder.
Recent
insights
evolve
from
static
view
morphologically
defined
tangles
driving
towards
more
dynamic,
biochemical
which
intermediary
soluble
Aβ
oligomers
fragments
considered
main
mediators
neurotoxicity.
The
relevance
pathways,
centered
on
toxic
Aβ,
cleavage
nucleation
tau,
general
proteostasis
neurons,
then
becomes
obvious.
Blocking
or
stimulating
provide,
have
potential
to
interesting
drug
targets,
raises
hope
will
be
able
cure
dreadful
