-
Cognition Research in Down Syndrome: The Turning Tide in
Defining and Delivering Treatments
William Mobley University of California,
San Diego
-
v
MY BOSSES
-
2) Discover genes and mechanisms
3) Create treatments
1) Define the problems
4) Deliver treatments
THE APPROACH
THE BOSS
-
Hypothesis Extra Gene(s)
Abnormal Synapses
Cognitive Problems
Research Strategy Cognitive Phenotype
Treatment Gene(s) &/or Mechanism
-
Mouse Models of DS Hsa21
Mmu16
Lipi
Mrpl39
App
Sod1
Cbr1
Fam3b Zfp295 Umodl1 Abcg1 U2af1 Rrp1b Prmt2
Pdxk
Dp(16)1Yey
Ts65Dn
Ts1Cje
Ts1Rhr
Dp(17)1Yey
Dp(10)1Yey
DSC
R
DSC
R
Mmu17
Mmu10
TTS
-
Increased Inhibition
Neurodegeneration
Neuronal Circuits: Double Trouble in Down Syndrome
NTF Signaling
-
Excitatory Inhibitory
Balancing Excitation and Inhibition Glutamate
GABA
-
GABAergic Neurobiology in Hippocampus
Larger GABAergic synapses. Molecular evidence for increased
GABAergic
neurotransmission. Physiological evidence for increased
GABAergic
neurotransmission Cognitive performance is rescued using
antagonists of GABA A or B receptors. Evidence implicating
increased gene dose for
Girk2.
-
Hypothesis Extra Gene(s)
Abnormal Synapses
Cognitive Problems
Research And Treatment Strategy Cognitive Phenotype
Treatment Gene(s) &/or Mechanism
Abnormal Learning & Memory
Increased Inhibition
Reduce Inhibition
-
Targeting Inhibition in Down Syndrome
GABA
GABA A Type Receptors
GABA B Type Receptors
Girk2 Channel
?
?
?
-
Targets to Modulate/Normalize Inhibition in DS
Selectively reduce activity of GABA A receptors Roche trial of
an inverse agonist for this subunit
Selectively reduce activity of GABA B receptors Compounds exist.
In discussions with industry
Selectively reduce activity of Girk2 channels Must screen for
compounds Other approaches being considered
-
Increased Inhibition
Neurodegeneration
Neuronal Circuits: Double Trouble in Down Syndrome
NTF Signaling
-
Pathology of AD in DS
The pathology of AD emerges in everyone with DS
-
Signaling Endosomes Carry Trophic Signals
-
Early Endosomes Enlarged in Ts65Dn mice
Cataldo A M et al. J. Neurosci. 2003;23:6788-6792
-
Increased App Gene Dose is Necessary for Decreased Endosomal
Tranport and for
Degeneration of BFCNs
Salehi et al, Neuron 2006; 51(1): 2942
-
Linking APP Gene Dose to Neurodegeneration
APP gene dose
Axonal transport
Neurodegeneration
-
AICD
-CTF
-CTF
GFP
GFP
GFP
GFP
A
A APP
APP and its Products - Finding the Culprit
+
+
+
A APP
GFP
GFP
+
_ _
-
Hypothesis Extra Gene(s)
Abnormal Synapses
Cognitive Problems
Research Strategy Cognitive Phenotype
Treatment Gene(s) &/or Mechanism
Age-Related Abnormal Learning & Memory
APP Gene Dose & Degeneration
Decrease APP, Modify Processing, or Restore Connections
-
Targets to Treat or Prevent AD in DS Selectively reduce the
effect of increased
expression of the gene for APP Through reducing the levels of
APP mRNA
Antisense Oligonucleotides specific for APP Through an antibody
to reduce A levels
AC Immune-trial planned Through restoring levels of NE and
other
neurotransmitters Hope to pursue this approach
Through changing processing of APP e.g. GSMs New class just
discovered at UCSD
-
Vaccine Treatment Rescued Memory Deficits in Novel Object
Recognition and Contextual
Fear Conditioning
40
60
80
100
2NTs65Dn
DS-01Vehicle
**
Dis
crim
inat
ion
inde
x (D
I) (%
)
0
10
20
30
40
50 2NTs65Dn
DS-01Vehicle Vehicle DS-01 Vehicle DS-01
***
Training Cuedmemory
Contextualmemory
Free
zing
(%)
B
C
A
0
500
1000
1500
2000
2500
DS-01Vehicle
**
Tota
l dis
tanc
e (c
m/1
0min
)
-
Targets to Treat or Prevent AD in DS Selectively reduce the
effect of increased
expression of the gene for APP Through reducing the levels of
APP mRNA
Antisense Oligonucleotides specific for APP Through an antibody
to reduce A levels
AC Immune-trial planned Through restoring levels of NE and
other
neurotransmitters Hope to pursue this approach
Through changing processing of APP e.g. GSMs New class just
discovered at UCSD
-
Newly Discovered Modulators of -Secretase Impact A Peptide
Production: Shorter Peptides/ Less Toxicity
GSMs also reduce the level of -CTFs
-
Increased Inhibition
Disrupted Axonal Function
Neuronal Circuits: Double Trouble in Down Syndrome
NTF Signaling 3 Targets 4 Targets
-
Pavel Alexander
Ahmad Chengbiao
The Investigators
Mike
-
Rachel
Steve
April
-
Xiaobei
Wei
Ricardo
-
Acknowledgements
Supported by: -Down Syndrome Research and Treatment Foundation
-National Institutes of Health
-Larry L Hillblom Foundation -Thrasher Foundation -Alzheimers
Association -Cure Alzheimers Fund
