© J. Poirier 2022
Le noyeau de l’équipe et les publications récentes
Brain
Reinnervation
and
Apolipoprotein
E
Neurobiology:
The
initial
phase
of
our
research
program
has
been
to
identify
key
mRNAs
involved
in
synaptic
remodelling
in
the
injured
adult
rodent
brain.
In
an
article
published
in
Proc.
Natl.
Acad.
Sci.
87:303
,
we
documented
the
fact
that
a
limited
numbers
of
mRNAs
of
moderate
prevalence
exhibit
significant
induction
during
the
active
phase
of
reinnervation
in
the
experimentally
deafferented
rat
hippocampus
(a
partial
model
of
Alzheimer's
disease
pathology).
The
most
important
transcript
identified
during
follow-up
cDNA
screenings
turned
out
to
be
a
protein
known
as
apolipoprotein
E
(apoE),
a
well-
characterized cholesterol transporter produced locally in the brain.
Apolipoprotein
E4
and
the
Pathophysiology
of
Alzheimer’s
disease
:
In
a
follow-up
series
of
studies
in
neurodegenerative
diseases,
we
published
a
breakthrough
report
in
the
Lancet
342:
697
where
we
reported
that
sporadic
cases
with
Alzheimer's
disease
(AD)
exhibit
an
abnormally
high
incidence
of
a
normally
rare
apoE
allele
referred
to
as
the
apoE4.
Follow-up
publications
by
our
team
demonstrated
a
potent
apoE4-gene
dose
effect
on
:
a)
age
of
onset,
b)
rate
of
progression,
c)
risk
of
developing
the
disease
and
more
importantly,
d)
on the cholinergic status and integrity in the brain of sporadic Alzheimer’s disease subjects:
Proc. Natl. Acad. Sci. 92
:
12260,
Lancet 347: 1091
,
J.A.M.A. 278: 1349
,
Proc. Natl. Acad. Sci. 98:
10966
.
Apolipoprotein
E
influences
the
Beta-Amyloid
Neurotoxicity
and
Metabolism:
In
more
recent
years,
we
uncovered
the
biological
connection
linking
the
so-called
beta
amyloid
cascade
hypothesis
of
AD
and
apolipoprotein
E
metabolism
in
the
pathophysiology
of
Alzheimer’s
disease.
Using
various
techniques,
models
and
approaches,
we
documented
the
apoE/beta
amyloid
relationship
in
vitro
and
in
vivo
.
The
studies
were
published
in
Nature
387:
500
,
J.
Neurochem.
66:2410
,
J.
Neurochem.
70:1466
,
Brain
Research
Reviews
27: 199
Apolipoprotein
E4:
A
Pharmacogenomic
Marker
of
Drug
Efficacy
in
Alzheimer’s
disease:
Our
modest
but
significant
contribution
to
the
emerging
field
of
the
pharmacogenomics
prompted
several
pharmaceutical
corporations
(Eli
Lilly,
Bayer,
Parke
Davis,
Novartis
and
Smith
Kline
Beecham)
to
re-evaluate
their
clinical
drug
trial
designs
to
include
an
apoE
genotype
arm.
We
and
others
have
documented
on
multiple
occasions
the
fact
that
the
efficacy
of
several
memory
enhancers
(especially
cholinomimetics)
are
highly
dependent
upon
the
individual’s
apoE
or
BuChE
K
genotypes
Proc.
Natl.
Acad.
Sci.
92:
12260
,
Neurology
50:
669,
Curr.
Pharmacogen.
8:
63
this
key
contribution
to
canadian
translation
research
effort
was
recognized
by
the
Galien
1996
Prize
and
Genesis
Awards 2010
Cholesterol
Metabolism
as
Therapeutic
Target
for
the
Treatment
of
Alzheimer’s
Disease:
As
early
as
1993,
we
proposed
that
the
reduction
in
apoE
concentrations
reported
in
the
blood
and
brain
of
apoE4
allele
carriers
could
be
alleviated
by
drugs
that
specifically
promote
apoE
synthesis
and
secretion
in
the
CNS.
Building
on
the
approach,
we
identified
three
different
agents
(out
of
several
hundreds) with strong apoE inducing capacity: estrogen, indomethacin and probucol
(
Eur. J. Neurosci. 18: 1
,
Neuroscience 121: 99
,
Alz.
Dem.
4:
591
,
Curr
Alz
Res
5:33
)
.
Independently
of
this
work,
these
three
compounds
had
been
shown
to
reduce
the
risk
of
developing
AD
in
several
epidemiological
studies
ran
in
the
US,
Europe
and
Asia.
As
a
consequence,
we
choose
to
focus
on
the
drug
Probucol,
a
potent
cholesterol-lowering
agent
for
efficacy
and
safety
reasons.
In
a
small
proof-of-principal
study
performed
in
Montreal
(
Adv.
Behav.
Biol.
51:
39
,
Trends
Mol.
Medicine
9:94
,
Neurobiol.
Aging
2014
),
we
discovered
that
a
6-month
treatment
with
Probucol
in
mild-tomoderate
AD
stopped
disease
progression
in
the
majority
of
the
12
patients
enrolled
in
the
study
and
“improved”
the
activities of daily living for the entire group.
CSF
Biomarkers
of
AD
Progression
in
“at
risk”
Asymptomatic
Subjects
:
Combining
genomic
information
(GWAS,
eQTL),
multiple
cohort
analyses
and
new
sensitive
bioassays
(OLINK,
LC/MS
/MS,
SimoA
and
Luminex),
we
successfully
documented
a
series
of
novel
CNS
biomarkers
and
genetic
risk
factors
that
modulate
AD
pathology
in
the
pre-symptomatic
phase
of
AD
(
JAMA
Neurol. 75:5:608-619, Alzheimer & Dementia 14:787-796, Nature Comm.10:2240-2255, Alzheimer and Dementia 15: 742-753
)
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