Nature,
Journal Year:
2023,
Volume and Issue:
625(7993), P. 119 - 125
Published: Nov. 29, 2023
Abstract
Intermediate
species
in
the
assembly
of
amyloid
filaments
are
believed
to
play
a
central
role
neurodegenerative
diseases
and
may
constitute
important
targets
for
therapeutic
intervention
1,2
.
However,
structural
information
about
intermediate
has
been
scarce
molecular
mechanisms
by
which
amyloids
assemble
remain
largely
unknown.
Here
we
use
time-resolved
cryogenic
electron
microscopy
study
vitro
recombinant
truncated
tau
(amino
acid
residues
297–391)
into
paired
helical
Alzheimer’s
disease
or
chronic
traumatic
encephalopathy
3
We
report
formation
shared
first
filament,
with
an
ordered
core
comprising
302–316.
Nuclear
magnetic
resonance
indicates
that
same
adopt
rigid,
β-strand-like
conformations
monomeric
tau.
At
later
time
points,
disappears
observe
many
different
filaments,
structures
depend
on
reaction
conditions.
end
both
reactions,
most
disappear
cores
as
those
from
human
brains
remain.
Our
results
provide
insights
processes
primary
secondary
nucleation
assembly,
implications
design
new
therapies.
Science,
Journal Year:
2022,
Volume and Issue:
375(6577), P. 167 - 172
Published: Jan. 14, 2022
Hi-res
view
of
human
Aβ42
filaments
Alzheimer’s
disease
is
characterized
by
a
loss
memory
and
other
cognitive
functions
the
filamentous
assembly
Aβ
tau
in
brain.
The
peptides
into
that
end
at
residue
42
central
event.
Yang
et
al
.
used
electron
cryo–electron
microscopy
to
determine
structures
from
brain
(see
Perspective
Willem
Fändrich).
They
identified
two
types
related
S-shaped
filaments,
each
consisting
identical
protofilaments.
These
will
inform
development
better
vitro
animal
models,
inhibitors
assembly,
imaging
agents
with
increased
specificity
sensitivity.
—SMH
Abundant
filamentous
inclusions
of
tau
are
characteristic
more
than
20
neurodegenerative
diseases
that
collectively
termed
tauopathies.
Electron
cryo-microscopy
(cryo-EM)
structures
amyloid
filaments
from
human
brain
revealed
distinct
folds
characterise
many
different
diseases.
A
lack
laboratory-based
model
systems
to
generate
these
has
hampered
efforts
uncover
the
molecular
mechanisms
underlie
Here,
we
report
in
vitro
assembly
conditions
with
recombinant
replicate
both
Alzheimer's
disease
(AD)
and
chronic
traumatic
encephalopathy
(CTE),
as
determined
by
cryo-EM.
Our
results
suggest
post-translational
modifications
modulate
filament
assembly,
previously
observed
additional
densities
AD
CTE
may
arise
presence
inorganic
salts,
like
phosphates
sodium
chloride.
In
into
disease-relevant
will
facilitate
studies
determine
their
roles
diseases,
well
development
compounds
specifically
bind
or
prevent
formation.
Molecular Neurodegeneration,
Journal Year:
2022,
Volume and Issue:
17(1)
Published: April 7, 2022
Abstract
Background
Tauopathies
are
a
class
of
neurodegenerative
disorders
characterized
by
neuronal
and/or
glial
tau-positive
inclusions.
Main
body
Clinically,
tauopathies
can
present
with
range
phenotypes
that
include
cognitive/behavioral-disorders,
movement
disorders,
language
and
non-specific
amnestic
symptoms
in
advanced
age.
Pathologically,
be
classified
based
on
the
predominant
tau
isoforms
inclusion
bodies
(i.e.,
3R,
4R
or
equal
3R:4R
ratio).
Imaging,
cerebrospinal
fluid
(CSF)
blood-based
biomarkers
have
potential
to
used
as
routine
diagnostic
strategy
evaluation
patients
tauopathies.
As
strongly
linked
neuropathologically
genetically
protein
abnormalities,
there
is
growing
interest
pursuing
tau-directed
therapeutics
for
disorders.
Here
we
synthesize
emerging
lessons
from
clinical,
pathological,
genetic,
experimental
studies
toward
unified
concept
these
may
accelerate
therapeutics.
Conclusions
Since
still
untreatable
diseases,
efforts
been
made
depict
clinical
pathological
characteristics,
identify
biomarkers,
elucidate
underlying
pathogenesis
achieve
early
diagnosis
develop
disease-modifying
therapies.
Nature,
Journal Year:
2022,
Volume and Issue:
605(7909), P. 310 - 314
Published: March 28, 2022
Abstract
Many
age-dependent
neurodegenerative
diseases,
such
as
Alzheimer’s
and
Parkinson’s,
are
characterized
by
abundant
inclusions
of
amyloid
filaments.
Filamentous
the
proteins
tau,
amyloid-β,
α-synuclein
transactive
response
DNA-binding
protein
(TARDBP;
also
known
TDP-43)
most
common
1,2
.
Here
we
used
structure
determination
cryogenic
electron
microscopy
to
show
that
residues
120–254
lysosomal
type
II
transmembrane
106B
(TMEM106B)
form
filaments
in
human
brains.
We
determined
structures
TMEM106B
from
a
number
brain
regions
22
individuals
with
deposits,
including
those
resulting
sporadic
inherited
tauopathies,
amyloid-β
amyloidoses,
synucleinopathies
TDP-43
proteinopathies,
well
frontal
cortex
3
normal
neurology
no
or
only
few
deposits.
observed
three
folds,
clear
relationships
between
folds
diseases.
correlated
presence
29-kDa
sarkosyl-insoluble
fragment
globular
cytoplasmic
inclusions,
detected
an
antibody
specific
carboxy-terminal
region
TMEM106B.
The
identification
brains
older,
but
not
younger,
indicates
they
manner.
Molecular Neurodegeneration,
Journal Year:
2021,
Volume and Issue:
16(1)
Published: Aug. 23, 2021
Abstract
Microtubule-associated
protein
tau
is
abnormally
aggregated
in
neuronal
and
glial
cells
a
range
of
neurodegenerative
diseases
that
are
collectively
referred
to
as
tauopathies.
Multiple
studies
have
suggested
pathological
species
may
act
seed
promotes
aggregation
endogenous
naïve
contributes
propagation
pathology.
While
they
share
common
feature,
tauopathies
distinct
from
one
another
with
respect
predominant
isoforms
accumulate
the
selective
vulnerability
brain
regions
cell
types
inclusions.
For
instance,
primary
present
pathology,
while
it
mostly
Alzheimer’s
disease
(AD).
Also,
morphologies
inclusions
can
greatly
vary
even
within
same
type,
suggesting
mechanisms
or
conformers
each
tauopathy.
Neuropathological
heterogeneity
across
challenges
our
understanding
pathophysiology
behind
seeding
aggregation,
well
efforts
develop
effective
therapeutic
strategies
for
AD
other
In
this
review,
we
describe
diverse
neuropathological
features
discuss
what
has
been
learned
experimental
mouse
models,
advanced
transcriptomics,
cryo-electron
microscopy
(cryo-EM)
on
biology
underlying
type-specific
