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ADITADITAD/PD Satellite Symposium
European Union Funding for Alzheimer Disease - The ADIT ProjectPrague, March 10, 2009
The poliovirus receptor PVRis associated with
Alzheimer Disease
Alessia Tarditi
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ADITADITAD/PD Satellite Symposium
European Union Funding for Alzheimer Disease - The ADIT ProjectPrague, March 10, 2009
Identified Identified targettarget
Confirmation of
differential
expression
Not experimental
evaluation
(IP, assays,
literature,
pathway)
Gene expression profile in human
tissues and postmortem
AD brain
Target analysis in AD animal
models and AD brain
Functional target
validation in rat
cortical neurons
TARGETTARGET
VALIDATEDVALIDATED
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ADITADITAD/PD Satellite Symposium
European Union Funding for Alzheimer Disease - The ADIT ProjectPrague, March 10, 2009
Rat cortical neurons
Ab 25-35
4hours
Affymetrix Chip:
rat 230.2
≈ 31000 transcripts
-
ADITADITAD/PD Satellite Symposium
European Union Funding for Alzheimer Disease - The ADIT ProjectPrague, March 10, 2009
-
ADITADITAD/PD Satellite Symposium
European Union Funding for Alzheimer Disease - The ADIT ProjectPrague, March 10, 2009
0,00E+00
2,00E-03
4,00E-03
6,00E-03
8,00E-03
1,00E-02
No
rma
lized
ex
pre
ss
ion
levels
BRAIN AREAS
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ADITADITAD/PD Satellite Symposium
European Union Funding for Alzheimer Disease - The ADIT ProjectPrague, March 10, 2009
* P
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ADITADITAD/PD Satellite Symposium
European Union Funding for Alzheimer Disease - The ADIT ProjectPrague, March 10, 2009
AD cortexControl case without
brain pathology- cortex
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ADITADITAD/PD Satellite Symposium
European Union Funding for Alzheimer Disease - The ADIT ProjectPrague, March 10, 2009
PVR positive astrocytes
(associated with amyloid plaque)
PVR positive neurons
(associated with amyloid plaque)
-
ADITADITAD/PD Satellite Symposium
European Union Funding for Alzheimer Disease - The ADIT ProjectPrague, March 10, 2009
NeuN
merge
PVR
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ADITADITAD/PD Satellite Symposium
European Union Funding for Alzheimer Disease - The ADIT ProjectPrague, March 10, 2009
A CB
Stage A: basal portions of the isocortex
Stage B: all isocortical association areas
Stage C: all areas of the isocortex[Braak and Braak, Acta Neuropathologica, 1991]
0
1
2
3
O A/B C
Sc
ore
fo
r P
VR
ne
uro
ns
Braak score for amyloid deposits
n=2 n=6 n=9
Score table for PVR
positive neurons:
total count
whole sectionscore
0 0
1-5 1
6-19 2
>20 3
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ADITADITAD/PD Satellite Symposium
European Union Funding for Alzheimer Disease - The ADIT ProjectPrague, March 10, 2009
0
1
2
3
O A/B C
PVR-positive neurons
[adapted from Hoozemans et al., Curr Pharm Des. 2008]
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ADITADITAD/PD Satellite Symposium
European Union Funding for Alzheimer Disease - The ADIT ProjectPrague, March 10, 2009
GFAP
merge
PVR
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ADITADITAD/PD Satellite Symposium
European Union Funding for Alzheimer Disease - The ADIT ProjectPrague, March 10, 2009
[adapted from Hoozemans et al., Curr Pharm Des. 2008]
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ADITADITAD/PD Satellite Symposium
European Union Funding for Alzheimer Disease - The ADIT ProjectPrague, March 10, 2009
[adapted from Hoozemans et al., Curr Pharm Des. 2008]
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ADITADITAD/PD Satellite Symposium
European Union Funding for Alzheimer Disease - The ADIT ProjectPrague, March 10, 2009
Scrambled siRNA
P53 siRNA
PVR siRNA
60 65 70 75 80 85
X1=PVR
X1=TNFR12A
X1=p53
X1=scr
20071120 exp1.xls
3 groups have population marginal means significantly different from X1=scr
60 65 70 75 80 85
X1=PVR
X1=TNFR12A
X1=p53
X1=scr
20071120 exp1.xls
3 groups have population marginal means significantly different from X1=scr
Two-Way ANOVA followed bya multiple comparison test
PVR
scrambled
p53
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ADITADITAD/PD Satellite Symposium
European Union Funding for Alzheimer Disease - The ADIT ProjectPrague, March 10, 2009
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ADITADITAD/PD Satellite Symposium
European Union Funding for Alzheimer Disease - The ADIT ProjectPrague, March 10, 2009
PVR +PVR -
White bar = PVR -
Grey bar= PVR +
(* p
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ADITADITAD/PD Satellite Symposium
European Union Funding for Alzheimer Disease - The ADIT ProjectPrague, March 10, 2009
Neurons
Astrocytes
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ADITADITAD/PD Satellite Symposium
European Union Funding for Alzheimer Disease - The ADIT ProjectPrague, March 10, 2009
0
1
2
3
O A/B C
PVR
pRB
Nu
mb
er
of
pR
b n
eu
ron
s (
per
mm
2)
Nu
mb
er
of
Ab
pla
qu
es
(10x, p
er
mm
2)
(av
era
ge ±
SE
M)
n=7 n=17 n=16
neuron
Score for PVR
positive neurons
n=2 n=6 n=9
-
+Nectin- bound PVR -
p < 0.001
scrambled PVR siRNA
p < 0.01
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ADITADITAD/PD Satellite Symposium
European Union Funding for Alzheimer Disease - The ADIT ProjectPrague, March 10, 2009
