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Lysosomal dysfunction in a mouse model of Sandhoff disease leads to accumulation of ganglioside-bound amyloid-β peptide.
[gm1 gangliosidosis]
Alterations
in
the
lipid
composition
of
endosomal-lysosomal
membranes
may
constitute
an
early
event
in
Alzheimer
's
disease
(
AD
)
pathogenesis
.
In
this
study
,
we
investigated
the
possibility
that
GM
2
ganglioside
accumulation
in
a
mouse
model
of
Sandhoff
disease
might
be
associated
with
the
accumulation
of
intraneuronal
and
extracellular
proteins
commonly
observed
in
AD
.
Our
results
show
intraneuronal
accumulation
of
amyloid-β
peptide
(
Aβ
)
-
like
,
α-synuclein-like
,
and
phospho-tau-like
immunoreactivity
in
the
brains
of
β-hexosaminidase
knock-out
(
HEXB
KO
)
mice
.
Biochemical
and
immunohistochemical
analyses
confirmed
that
at
least
some
of
the
intraneuronal
A
β-like
immunoreactivity
(
iA
β-LIR
)
represents
amyloid
precursor
protein
C-
terminal
fragments
(
APP
-CTFs
)
and
/
or
Aβ
.
In
addition
,
we
observed
increased
levels
of
Aβ
40
and
Aβ
42
peptides
in
the
lipid-associated
fraction
of
HEXB
KO
mouse
brains
,
and
intraneuronal
accumulation
of
ganglioside-bound
Aβ
(
GAβ
)
immunoreactivity
in
a
brain
region-
specific
manner
.
Furthermore
,
α-synuclein
and
APP
-CTFs
and
/
or
Aβ
were
found
to
accumulate
in
different
regions
of
the
substantia
nigra
,
indicating
different
mechanisms
of
accumulation
or
turnover
pathways
.
Based
on
the
localization
of
the
accumulated
iA
β-LIR
to
endosomes
,
lysosomes
,
and
autophagosomes
,
we
conclude
that
a
significant
accumulation
of
iA
β-LIR
may
be
associated
with
the
lysosomal-autophagic
turnover
of
Aβ
and
fragments
of
APP
-containing
Aβ
epitopes
.
Importantly
,
intraneuronal
GAβ
immunoreactivity
,
a
proposed
prefibrillar
aggregate
found
in
AD
,
was
found
to
accumulate
throughout
the
frontal
cortices
of
postmortem
human
GM
1
gangliosidosis
,
Sandhoff
disease
,
and
Tay-
Sachs
disease
brains
.
Together
,
these
results
establish
an
association
between
the
accumulation
of
gangliosides
,
autophagic
vacuoles
,
and
the
intraneuronal
accumulation
of
proteins
associated
with
AD
.
Diseases
Validation
Diseases presenting
"proposed prefibrillar aggregate"
symptom
gm1 gangliosidosis
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