Cognition Research in Down Syndrome: The Turning Tide in Defining and Delivering Treatments

William Mobley University of California, San Diego

MY BOSSES

THE APPROACH
1) Define the problems 2) Discover genes and mechanisms

THE BOSS

4) Deliver treatments

3) Create treatments

Hypothesis
Extra Gene(s) Abnormal Synapses Cognitive Problems

Research Strategy
Treatment Gene(s) &/or Mechanism Cognitive Phenotype

Mouse Models of DS
Hsa21 Mmu16
Lipi

TTS Dp(16)1Yey

Mrpl39 App DSCR Sod1 Cbr1 Fam3b Zfp295 Umodl1 Abcg1 U2af1 Rrp1b Prmt2

Ts65Dn Ts1Cje Ts1Rhr

DSCR

Mmu17

Dp(17)1Yey

Mmu10

Dp(10)1Yey
Pdxk

Neuronal Circuits: Double Trouble in Down Syndrome

Increased Inhibition
NTF Signaling

Neurodegeneration

Balancing Excitation and Inhibition

Glutamate
Excitatory

GABA
Inhibitory

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 Cognitive Phenotype
Abnormal Learning & Memory

Research And Treatment Strategy

Treatment Gene(s) &/or Mechanism
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

Neuronal Circuits: Double Trouble in Down Syndrome

Increased Inhibition
NTF Signaling

Neurodegeneration

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

APP and its Products - Finding the Culprit APP APP -CTF -CTF AICD A A A GFP

+ GFP + GFP + _ GFP _ GFP +

Hypothesis
Extra Gene(s) Abnormal Synapses Cognitive Problems Cognitive Phenotype
Age-Related Abnormal Learning & Memory

Research Strategy
Treatment Gene(s) &/or Mechanism
Decrease APP, APP Gene Dose Modify & Degeneration 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

A
Total distance (cm/10min)
2500 2000 1500 1000 500 0 Vehicle DS-01

B
* *
100

Discrimination index (DI) (%)

80 60 40 Vehicle

2N Ts65Dn

DS-01

C
Freezing (%)

50 40 30 20 10 0
Vehicle DS-01 Vehicle DS-01 Vehicle

**

2N Ts65Dn

DS-01

Training

Cued memory

Contextual memory

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

Neuronal Circuits: Double Trouble in Down Syndrome

Increased Inhibition
3 Targets NTF Signaling 4 Targets

Disrupted Axonal Function

The Investigators

Pavel Alexander

Ahmad Mike

Chengbiao

Steve

Rachel

April

Wei Xiaobei 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