1. Exploring the Neurobiology of Cognitive Dysfunction in Down Syndrome William Mobley M.D., Ph.D. and Craig Garner Ph.D. Stanford University Center for Research and Treatment of Down Syndrome

2. The Center for Research and Treatment of Down Syndrome Helping People with Down Syndrome Live More Independent Lives

3. Defining the Problem Neurological manifestations of Down syndrome are disabling. Cognitive problems are significant -extend across the lifespan -development is globally slowed -marked involvement of memory, speech and language All people with Down syndrome show the neuropathology of Alzheimer’s disease by the age of 40 and many show further cognitive decline.

4. Creating a research community that listens to parents and to people with Down syndrome. Building a research enterprise that brings the best scientists and clinicians to work on the problem and that uses the most modern technologies. Defining research priorities on the basis of what will lead to effective treatments. Funding this work while insisting that researchers share data and credit. Rapidly moving new discoveries to new treatments. The Center for Research and Treatment of Down Syndrome

5. Small Change in Cognitive Capability could have Profound impact on Independence % Population Independent LivingDependent Living 15%

6. Attack from several directions 15% Cognitive Improvement Sleep CBT Brain

7. Down Syndrome – Important Facts Advances in Down syndrome have not kept pace with those in other fields -Too complex to understand -Too difficult to study -Too late to be of help

8. Federal research dollars per patient 0 350 700 Alzheimer’sAutismDown Syndrome ALS Down Syndrome – Important Facts The Investment in Research is Tiny in Comparison to other Disorders

9. Neurons Cognition Neuronal systems Genes Development Clinical trials Industry Delivery Health Care Neuroscience Translating Research Advances in DS NIH Doesn’t Push: Industry Doesn’t Pull

10. Down Syndrome – The Conclusions People with Down syndrome have not been adequately served by the many advances that are revolutionizing our ability to understand and treat disorders of the nervous system. Without a fundamental change in research funding, and the culture in which it is carried out, there will be little progress in helping people with Down syndrome.

11. Neurons Cognition Neuronal systems Genes Development Clinical trials Industry Delivery Health Care Science Translating Research Advances in the Center for Down Syndrome Breaking Down Barriers Through Integration of Efforts

12. Stanford University Director: William Mobley Co-Director: Craig Garner Principle Investigators: Robert Malenka, Craig Garner, Irving Weissman, Barbara Sommer, Allan Reiss, Dan Madison, Emmanuel Mignot, William Mobley Associate Investigators: Pavel Belichenko, Alexander Kleschevnikov, Jean Delcroix, Ahmad Salehi, Subha Basu, Ke Zhan, Chengbiao Wu, Damien Colas, Fabian Fernandez, Martina Blank

13. DS Center Participants UCSF Charles Epstein Angela Villar UC Berkeley Lucia Jacobs Case Western Bruce Lamb Med Univ SC Kumar Sambamurti NYU Randy Nixon Johns Hopkins Roger Reeves UT Southwestern Luis Parada UCSD Eliezer Masliah Larry Goldstein Gorazd Stokin Harvard Weiming Xia

14. UNDERSTANDING AND TREATING DOWN SYNDROME -NOT TOO COMPLEX Because specific genes and mechanisms will be found to cause cognitive problems -NOT TOO DIFFICULT Because tools are available to find these genes and understand how an extra copy causes cognitive problems -NOT TOO LATE Because brain function can be modified, even in adults

15. Research Strategy Define the Abnormality of Interest in Down Syndrome Build the Model System to Recreate the Abnormality Find and Characterize the Abnormality in the Model Define the Gene(s) Pursue Treatments that Reduce the Expression of the Gene(s) or that Block the Mechanism Define the Mechanism

16. presynapse postsynapse

17. NEURONAL CIRCUITS ARE DISRUPTED IN DS x x DISRUPTED X X

18. A) Normal neonatal brain B) Down syndrome (DS; trisomy 21) (from Marin-Padilla, 1976). Synapse Structure is Abnormal in Individuals with Down Syndrome 10  m AB

19. Hypothesis That cognitive dysfunction in Down syndrome is due to abnormalities in the structure, function and maintenance of synapses and that each such abnormality is caused by the presence of an extra copy of a gene(s) on chromosome 21.

20. APP Grik1 Sod1 Gart Sim2 Dryk1a Ets2 Mx1 Sod1 Gart Sim2 Dryk1a Mx1 Ets2 APP Grik1 Sod1 Ts65DnTs1CjeMs1Ts65 A Mouse Model of Down Syndrome Gabpa These Mice Carry an Extra Copy of Many of the Genes Responsible For Down Syndrome

21. PP Sch MF CA1 A lv CA3 Entorhinal Cortex 1 2 3 Anatomy of Circuits in the Hippocampus: a Brain Region Critical for Learning and Memory Dentate Gyrus Cholinergic Neuron DGC Perforant Path

22. Mossy cell GABAergic neuron GABAergic neuron GL IML OML MML Cholinergic neuron DGC PP

23. Synaptic Structure and Function are Abnormal in Ts65Dn Mice Synaptic Structure and Function are Abnormal in Ts65Dn Mice 2N mice Glu GAB A ACh Ts65Dn mice ACh Glu GABA

24. Enlarged Synapses: Possible Causes Suppression of normal excitatory input leads to increased size of synapses. -what gene(s) are involved? -what mechanism(s) is responsible? -affecting developing neurons, mature neurons, or both?

25. Synaptic Structure and Function are Abnormal in Ts65Dn Mice Synaptic Structure and Function are Abnormal in Ts65Dn Mice 2N mice Glu GAB A ACh Ts65Dn mice ACh Glu GABA

26. Dentate Gyrus CA3 CA1 MF PP Inhibitory neuron Synaptic Plasticity Was Suppressed in Ts65Dn Mice Synaptic Plasticity was Restored by Blocking Inhibition Synapses Become More Efficient During Learning – Synaptic Plasticity Abnormal Synaptic Function in Ts65Dn Mice

27. Proposed Mechanism for Decreased Synaptic Plasticity in Ts65Dn Increased inhibition Suppression of Learning Decreased Synaptic Plasticity

28. Research Strategy Define the Abnormality of Interest in Down Syndrome Build the Model System to Recreate the Abnormality Find and Characterize the Abnormality in the Model Define the Gene(s) Pursue Treatments that Reduce the Expression of the Gene(s) or that Block the Mechanism Define the Mechanism

29. Mossy cell GABA-ergic cell GABA-ergic cell GL IML PP OML MML Cholinergic neuron DGC

30. NTF

31. NEURONAL CIRCUITS ARE DISRUPTED IN DS x x DISRUPTED X X NTF

32. NGF Produced in Hippocampus Regulates the Differentiation, Survival and Maintenance of Cholinergic Neurons Hippocampus NGF Cholinergic Neuron These Cholinergic Neurons Degenerate In Alzheimer’s Disease and Down Syndrome

33. 2NTs65Dn Amount of NGF Transported 125 I-NGF Cholinergic Neurons Hippocampus Reduced Axonal Transport of NGF from the Hippocampus to Cholinergic Neurons in Ts65Dn

34. Candidate Genes for Failed NGF Retrograde Transport GABPA App ADAMTS1 ADAMTS5 PRED28 ZNF294 C21orf6 USP16 CCT8 GRIK1 CLDN17 CLDN8 TIAM1 SOD1 T APP Grik1 Sod1 Gart Sim2 Dryk1a Ets2 Mx1 Ts65Dn Gabpa

35. Ts65Dn: APP+/+/+ Ts65Dn: APP+/+/- 2N Percent Cell profile area (  m 2 ) 050 100 150200 250 300 0 10 20 30 40 50 60 0 20 40 60 80 100 NGF Transport (percent of 2N) * ** 2N Ts65Dn/APP++- Ts65Dn/APP+++ Ts65Dn/APP++- Ts65Dn/APP+++ Deleting One Copy of App in Ts65Dn Mice Markedly Enhances 125 I-NGF Transport and Prevents BFCN Atrophy

36. Research Strategy Define the Abnormality of Interest in Down Syndrome Build the Model System to Recreate the Abnormality Find and Characterize the Abnormality in the Model Define the Gene(s) Pursue Treatments that Reduce the Expression of the Gene(s) or that Block the Mechanism Define the Mechanism

37. A Proposal for Pathogenesis Increased APP Gene Expression Cholinergic Neuron Dysfunction and Degeneration Decreased NGF Transport

38. A Proposal for Pathogenesis Increased APP Gene Expression No Cholinergic Neuron Dysfunction and Degeneration Normal NGF Transport Treatment

39. Summary 1)Synapses are abnormal in mouse models of Down syndrome. 2)Considerable progress is anticipated with respect to defining the genes and mechanisms responsible. 3)Current studies will lead to attempts to correct defects in mice. 4)Because the changes detected in mice are relevant to those in people with Down syndrome, this work should guide and hasten the development of new treatments – and this is our ultimate goal.