Brain,
Год журнала:
2023,
Номер
146(10), С. 3969 - 3990
Опубликована: Май 15, 2023
Results
from
recent
clinical
trials
of
antibodies
that
target
amyloid-β
(Aβ)
for
Alzheimer's
disease
have
created
excitement
and
been
heralded
as
corroboration
the
amyloid
cascade
hypothesis.
However,
while
Aβ
may
contribute
to
disease,
genetic,
clinical,
imaging
biochemical
data
suggest
a
more
complex
aetiology.
Here
we
review
history
weaknesses
hypothesis
in
view
new
evidence
obtained
anti-amyloid
antibodies.
These
indicate
treatments
either
no
or
uncertain
effect
on
cognition.
Despite
importance
definition
argue
point
playing
minor
aetiological
role.
We
also
discuss
suggesting
concerted
activity
many
pathogenic
factors
propose
evolving
multi-factor
models
will
better
underpin
search
effective
strategies
treat
disease.
Proceedings of the National Academy of Sciences,
Год журнала:
2012,
Номер
109(5), С. 1737 - 1742
Опубликована: Янв. 17, 2012
N
-methyl-
d
-aspartate
receptors
(NMDARs)
mediate
critical
CNS
functions,
whereas
excessive
activity
contributes
to
neuronal
damage.
At
physiological
glycine
concentrations,
NMDAR
currents
recorded
from
cultured
rodent
hippocampal
neurons
exhibited
strong
desensitization
in
the
continued
presence
of
NMDA,
thus
protecting
calcium
overload.
Reducing
copper
availability
by
specific
chelators
(bathocuproine
disulfonate,
cuprizone)
induced
nondesensitizing
even
at
physiologically
low
concentrations.
This
effect
was
mimicked
by,
and
not
additive
with,
genetic
ablation
cellular
prion
protein
(PrP
C
),
a
key
copper-binding
CNS.
Acute
PrP
enzymatically
cleaving
its
cell-surface
GPI
anchor
yielded
similar
effects.
Biochemical
studies
electrophysiological
measurements
revealed
that
interacts
with
complex
copper-dependent
manner
allosterically
reduce
affinity
for
receptor.
Synthetic
human
Aβ
1–42
(10
nM–5
μM)
produced
an
identical
could
be
mitigated
addition
excess
ions
or
blockers.
Taken
together,
,
chelators,
inactivation
all
enhance
NMDAR,
giving
rise
pathologically
large
steady-state
neurotoxicity.
We
propose
role
one
limits
might
otherwise
promote
In
addition,
we
provide
unifying
molecular
mechanism
whereby
toxic
species
synaptic
injury,
least
part,
disrupting
normal
copper-mediated,
-dependent
inhibition
this
highly
calcium-permeable
glutamate
Brain,
Год журнала:
2023,
Номер
146(10), С. 3969 - 3990
Опубликована: Май 15, 2023
Results
from
recent
clinical
trials
of
antibodies
that
target
amyloid-β
(Aβ)
for
Alzheimer's
disease
have
created
excitement
and
been
heralded
as
corroboration
the
amyloid
cascade
hypothesis.
However,
while
Aβ
may
contribute
to
disease,
genetic,
clinical,
imaging
biochemical
data
suggest
a
more
complex
aetiology.
Here
we
review
history
weaknesses
hypothesis
in
view
new
evidence
obtained
anti-amyloid
antibodies.
These
indicate
treatments
either
no
or
uncertain
effect
on
cognition.
Despite
importance
definition
argue
point
playing
minor
aetiological
role.
We
also
discuss
suggesting
concerted
activity
many
pathogenic
factors
propose
evolving
multi-factor
models
will
better
underpin
search
effective
strategies
treat
disease.
