Chemical Reviews,
Journal Year:
2021,
Volume and Issue:
121(4), P. 2545 - 2647
Published: Feb. 5, 2021
Protein
misfolding
and
aggregation
is
observed
in
many
amyloidogenic
diseases
affecting
either
the
central
nervous
system
or
a
variety
of
peripheral
tissues.
Structural
dynamic
characterization
all
species
along
pathways
from
monomers
to
fibrils
challenging
by
experimental
computational
means
because
they
involve
intrinsically
disordered
proteins
most
diseases.
Yet
understanding
how
amyloid
become
toxic
challenge
developing
treatment
for
these
Here
we
review
what
computer,
vitro,
vivo,
pharmacological
experiments
tell
us
about
accumulation
deposition
oligomers
(Aβ,
tau),
α-synuclein,
IAPP,
superoxide
dismutase
1
proteins,
which
have
been
mainstream
concept
underlying
Alzheimer's
disease
(AD),
Parkinson's
(PD),
type
II
diabetes
(T2D),
amyotrophic
lateral
sclerosis
(ALS)
research,
respectively,
years.
Alzheimer s & Dementia,
Journal Year:
2020,
Volume and Issue:
17(4), P. 696 - 701
Published: Nov. 1, 2020
Abstract
Aducanumab
recently
underwent
two
large
phase
III
clinical
trials
that
were
stopped
prematurely
by
the
sponsor
Biogen.
One
trial
was
trending
positive
while
other
showed
no
benefits
from
aducanumab.
Post
hoc
analyses
led
to
assert
there
a
sufficient
efficacy
signal
justify
new
drug
application
as
treatment
for
Alzheimer's
disease.
The
claimed
subsets
of
participants
receiving
sufficiently
high
doses
aducanumab
demonstrated
in
both
trials.
In
contrast,
we
identified
alternative
accounts
apparent
post
subgroups
are
unrelated
dose
effects.
Biomarker
data
consistent
with
target
engagement,
but
evidence
presented
correlate
biomarker
changes
cognitive
benefits.
Our
analysis
supports
conduct
third,
high‐dose
Aducanumab's
dysfunction
disease
cannot
be
proven
divergent
outcomes.
Molecular Neurobiology,
Journal Year:
2020,
Volume and Issue:
57(12), P. 5026 - 5043
Published: Aug. 22, 2020
Understanding
how
gut
flora
influences
gut-brain
communications
has
been
the
subject
of
significant
research
over
past
decade.
The
broadening
term
"microbiota-gut-brain
axis"
from
"gut-brain
underscores
a
bidirectional
communication
system
between
and
brain.
microbiota-gut-brain
axis
involves
metabolic,
endocrine,
neural,
immune
pathways
which
are
crucial
for
maintenance
brain
homeostasis.
Alterations
in
composition
microbiota
associated
with
multiple
neuropsychiatric
disorders.
Although
causal
relationship
dysbiosis
neural
dysfunction
remains
elusive,
emerging
evidence
indicates
that
may
promote
amyloid-beta
aggregation,
neuroinflammation,
oxidative
stress,
insulin
resistance
pathogenesis
Alzheimer's
disease
(AD).
Illustration
mechanisms
underlying
regulation
by
pave
way
developing
novel
therapeutic
strategies
AD.
In
this
narrative
review,
we
provide
an
overview
their
dysregulation
Novel
insights
into
modification
as
preventive
or
approach
AD
highlighted.
International Journal of Biological Sciences,
Journal Year:
2021,
Volume and Issue:
17(9), P. 2181 - 2192
Published: Jan. 1, 2021
Extracellular
neuritic
plaques
composed
of
amyloid‑β
(Aβ)
protein
and
intracellular
neurofibrillary
tangles
containing
phosphorylated
tau
are
the
two
hallmark
proteins
Alzheimer's
disease
(AD),
separate
neurotoxicity
these
in
AD
has
been
extensively
studied.
However,
interventions
that
target
Aβ
or
individually
have
not
yielded
substantial
breakthroughs.
The
interest
interactions
between
is
increasing,
but
related
drug
investigations
their
infancy.
This
review
discusses
how
accelerates
phosphorylation
possible
mechanisms
pathways
by
which
mediates
toxicity.
also
describes
synergistic
effects
on
microglial
cells
astrocytes.
Studies
suggest
coexistence
to
mechanism
facilitates
propagation
aggregation
plaques.
mediate
cognitive
dysfunction
patients
with
AD.
In
summary,
this
summarizes
recent
data
interplay
promote
a
better
understanding
roles
pathological
process
provide
new
insights
into
against
Frontiers in Neurology,
Journal Year:
2020,
Volume and Issue:
10
Published: Jan. 10, 2020
Alzheimer's
disease
(AD),
a
common
neurodegenerative
in
the
elderly
and
most
prevalent
cause
of
dementia,
is
characterized
by
progressive
cognitive
impairment.
The
prevalence
AD
continues
to
increase
worldwide,
becoming
great
healthcare
challenge
twenty-first
century.
In
more
than
110
years
since
was
discovered,
many
related
pathogenic
mechanisms
have
been
proposed,
recognized
hypotheses
are
amyloid
tau
hypotheses.
However,
almost
all
clinical
trials
targeting
these
not
identified
any
effective
methods
treat
AD.
Scientists
gradually
moving
away
from
simple
assumption,
as
proposed
original
hypothesis,
new
theories
pathogenesis,
including
gamma
oscillations,
prion
transmission,
cerebral
vasoconstriction,
growth
hormone
secretagogue
receptor
1α
(GHSR1α)-mediated
mechanism,
infection.
To
place
findings
context,
we
first
reviewed
neuropathology
further
discussed
insights
pathogenesis
Frontiers in Immunology,
Journal Year:
2020,
Volume and Issue:
11
Published: March 31, 2020
Neuroinflammation
commences
decades
before
Alzheimer's
disease
(AD)
clinical
onset
and
represents
one
of
the
earliest
pathomechanistic
alterations
throughout
AD
its
continuum.
Large-scale
genome-wide
association
studies
point
out
several
genetic
variants
-
TREM2,
CD33,
PILRA,
CR1,
MS4A,
CLU,
ABCA7,
EPHA1,
HLA-DRB5-HLA-DRB1
potentially
linked
to
neuroinflammation.
Most
these
genes
are
involved
in
proinflammatory
intracellular
signaling,
cytokines/interleukins
cell
turn-over,
synaptic
activity,
lipid
metabolism,
vesicle
trafficking.
Proteomic
indicate
that
a
plethora
interconnected
aberrant
molecular
pathways,
set
off
perpetuated
by
TNF-α,
TGF-β,
IL-1β,
receptor
protein
Microglia
astrocytes
key
cellular
drivers
regulators
Under
physiological
conditions,
they
important
for
neurotransmission
homeostasis.
In
AD,
there
is
turning
pathophysiological
evolution
where
glial
cells
sustain
an
overexpressed
inflammatory
response
synergizes
with
amyloid-β
tau
accumulation,
drives
synaptotoxicity
neurodegeneration
self-reinforcing
manner.
Despite
strong
therapeutic
rationale,
previous
trials
investigating
compounds
anti-inflammatory
properties,
including
non-steroidal
drugs
(NSAIDs)
did
not
achieve
primary
efficacy
endpoints.
It
conceivable
study
design
issues,
lack
diagnostic
accuracy
biomarkers
target
population
identification
proof-of-mechanism
may
partially
explain
negative
outcomes.
However,
recent
meta-analysis
indicates
potential
biological
effect
NSAIDs.
this
regard,
candidate
fluid
neuroinflammation
under
analytical/clinical
validation,
i.e.
MCP-1,
IL-6,
TNF-α
complexes,
YKL-40.
PET
radio-ligands
investigated
accomplish
in-vivo
longitudinal
regional
exploration
Biomarkers
tracking
different
pathways
(body
matrixes)
along
brain
neuroinflammatory
endophenotypes
(neuroimaging
markers),
can
untangle
temporal-spatial
dynamics
between
other
mechanisms.
Robust
biomarker-drug
co-development
pipelines
expected
enrich
large-scale
testing
new-generation
active,
directly
or
indirectly,
on
targets
displaying
putative
disease-modifying
effects:
novel
NSAIDs,
AL002
(anti-TREM2
antibody),
anti-Aβ
protofibrils
(BAN2401),
AL003
(anti-CD33
antibody).
As
next
step,
taking
advantage
breakthrough
multimodal
techniques
coupled
systems
biology
approach
path
pursue
developing
individualized
strategies
targeting
framework
precision
medicine.
