• Save
Mobley
Upcoming SlideShare
Loading in...5
×
 

Mobley

on

  • 1,104 views

 

Statistics

Views

Total Views
1,104
Views on SlideShare
359
Embed Views
745

Actions

Likes
0
Downloads
0
Comments
0

4 Embeds 745

http://www.alzforum.org 739
http://alzforum.org 3
http://translate.googleusercontent.com 2
http://www.zespoldowna.info 1

Accessibility

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment
  • Elements of the Center. Define the most significant cognitive problems facing individuals with DS. Uses mouse models to phenocopy these problems, maps the critical genes and their mode of actions and then, together with industry, find effective treatments that can make a difference.
  • Elements of the Center. Define the most significant cognitive problems facing individuals with DS. Uses mouse models to phenocopy these problems, maps the critical genes and their mode of actions and then, together with industry, find effective treatments that can make a difference.
  • Fig 2. AT methodologies. A. AT imaging achieves superlative resolution and depth-independence of sensitivity based on planar arraying, staining and imaging of physical sections. B. The AT proteomic imaging cycle involves multiple rounds of immunostaining, imaging, and antibody elution, allowing collection of data from up to at least 40 antibody channels in a single ribbon of sections at full resolution.
  • This schematic diagram shows a crosscut of the hippocampus of the mouse brain. The hippocampus is selectively affected in people with Down syndrome. The hippocampus is much involved in the processing of information leading to learning and memory. The hippocampus has a circuit that consists of three neurons, each of which is excitatory. The circuit is activated by input from the entorhinal cortex and sends its information from the hippocampus back to the cortex. Neurons from the entorhinal cortex send their axons through the perforant pathway (green line) to hippocampus. Their axons synapse with the granule cells of the dentate gyrus (red neuron). The granule cells send their axons to synapse with pyramidal cells (black) lying in the CA3 region of the hippocampus. Finally, the pyramidal cells in the CA3 region send axons to synapse on the pyramidal cells (black) in the CA1 region. This three neuron circuit is important for learning and encoding and memory.

Mobley Mobley Presentation Transcript

  • Exploring the Neurobiology of Down Syndrome: From Science to Medicine Center for Down Syndrome Research and Treatment University of California, San Diego
  • The Investigators Mike Pavel Alexander Ahmad Chengbiao
  • Steve Wagner
  • v OUR BOSSES
  • Discover genes and mechanisms Create treatments Define the problems Deliver treatments THE PLAN THE BOSS
  • Center for Down Syndrome Research and Treatment at UCSD
    • Created to accelerate progress and enhance care for people with Down syndrome by linking clinical care, clinical research and basic science.
    Clin Care Children 0-5 Clin Care Adults Clin Care Children 5-18 Global Research UCSD Research Comm Outreach Pharma Clinical Trials
  •  
  • Defining the Problems in Down Syndrome
    • Disabling neurological manifestations
    • Extend across the lifespan
    • Cognitive problems:
      • In children
      • -development is slowed
      • -deficits in learning, memory, language
      • In adults
      • - Alzheimer’s neuropathology by age 40
      • - Most show dementia in the 60s.
  •  
  •  
  • X X Hypothesis Extra Gene(s) Abnormal Synapses Cognitive Problems Research Strategy Cognitive Phenotype Treatment Gene(s) &/or Mechanism
  • APP Grik1 Sod1 Gart Sim2 Dryk1a Ets2 Mx1 Sod1 Gart Sim2 Dryk1a Mx1 Ets2 APP Grik1 Sod1 Ts65Dn Ts1Cje Ms1Ts65 A Mouse Model of Down Syndrome Gabpa
  • Defining the Genetic Basis for Cognitive Deficits in Mouse Models of Down Syndrome
    • An imbalance in excitation and inhibition
      • The mechanism is being explored
      • A gene segment has been identified
      • Drugs that reduce GABAergic transmission enhance cognition
    • Inadequate maintenance of circuits
      • One gene has been identified
      • The mechanism is being explored
    Neuronal Circuits Are Disrupted In Down Syndrome
  • Inhibition Is Excessive This Produces and Imbalance In E/I Ratio + _ - + Glutamate GABA
  • Excitatory and Inhibitory Synapses in 2 N versus Ts65Dn Mice 0.5  m b
  • Array Tomography Methodology: Micheva et al 2007
  • Evidence for Increased Inhibition Disrupting Plasticity PP PP
  • Defining the Genetic Basis for Cognitive Deficits in Mouse Models of Down Syndrome
  • Hypothesis Extra Gene(s) Abnormal Synapses Cognitive Problems Research Strategy Cognitive Phenotype Treatment Gene(s) &/or Mechanism Abnormal Learning & Memory Inc. Inhibition Treat Inc. Inhibition
  • Targets to Modulate/Normalize Inhibition in DS
    • Selectively reduce activity of GABA A receptors
      • Compounds do exist that target this type
      • In active dialogue with Roche
      • They are considering a clinical trial
    • Selectively reduce activity of GABA B receptors
      • Compounds also exist for these receptors
      • No industrial partner as yet
    • Selectively reduce activity of channels that increase inhibition – for which there is an extra copy in DS
      • Extremely attractive, but we have no selective compounds
      • No industry partner as yet
    • An imbalance in excitation and inhibition
      • The mechanism is being explored
      • A gene segment has been identified
      • Drugs that reduce GABAergic transmission enhance cognition
    • Inadequate maintenance of circuits
      • One gene has been identified
      • The mechanism is being explored
    Neuronal Circuits Are Disrupted In Down Syndrome
  • Neurotrophic Factor Signals Are Critical for Survival and Maintenance of Neurons And The Circuits In Which They Work Signaling Endosomes Carry Trophic Signals
  • PP Sch MF CA1 A lv CA3 Entorhinal Cortex 1 2 3 Cortex DG BFCN DGC Perforant Path Raphe Locus Defining A Role For Neurotrophic Factors in Hippocampal Circuits Dysfunction in Down Syndrome APP Gene Dose Plays A Role
    • Decreased Trophic Support Leads to Dysfunction and Death of Neurons
    Neuronal Circuits Fail During Aging Normal Down Syndrome + - + _ supply demand supply demand
  •  -secretase Plays a Critical Role in APP Processing and in Generation of A 
    •  eta toxicity is likely to arise from an increase in the ratio of 42/40
    •  -secretase is ultimately responsible for this ratio
      •  site cleavage results in several A  peptides (A  40 , A  42 , A  37 , A  38 )
      •  site cleavage results in release of AICD and A  49/50
    •  secretase has many substrates
  • Impact of Increased APP Gene Dose: Focus on Processing APP
  • 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
    • Selectively reduce the effect of increased expression of the gene for APP
      • Through changing processing of APP– e.g. GSMs –
        • New class just discovered at UCSD
      • Through an antibody to reduce A  levels –
        • Recent success working with AC Immune
      • Through restoring levels of NE and other neurotransmitters –
        • A trial being planned with Chelsea
    • An imbalance in excitation and inhibition
      • The mechanism is being explored
      • A gene segment has been identified
      • Drugs that reduce GABAergic transmission enhance cognition
    • Inadequate maintenance of circuits
      • One gene has been identified
      • The mechanism is being explored
    Neuronal Circuits Are Disrupted In Down Syndrome There are now 6 rational targets to pursue
  • Opportunities and Challenges
    • The opportunities for understanding and treating the disorders of children and adults are many.
    • We are on the cusp of studies that may enhance the lives of people with Down syndrome.
    • Studies in Down syndrome may open up new vistas for treating many other disorders, most notably intellectual deficiency in children and Alzheimer disease.
    • People with Down syndrome have much to teach us all.
  • Opportunities and Challenges
    • We do not know that what is true in models is true in man.
    • We need to build a research program that links observations in models to man.
    • We need to understand better the natural history and the needs of people with Down syndrome.
    • It will be essential to build a stronger more diverse community to achieve success.
  • Acknowledgements Supported by: -Down Syndrome Research and Treatment Foundation -National Institutes of Health -Larry L Hillblom Foundation -Thrasher Foundation -Alzheimer’s Association -Cure Alzheimer’s Fund
  •  
  •  
  •