Documente Academic
Documente Profesional
Documente Cultură
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
DSCR
Mmu17
Dp(17)1Yey
Mmu10
Dp(10)1Yey
Pdxk
Increased Inhibition
NTF Signaling
Neurodegeneration
Glutamate
Excitatory
GABA
Inhibitory
Hypothesis
Extra Gene(s) Abnormal Synapses Cognitive Problems Cognitive Phenotype
Abnormal Learning & Memory
Reduce Inhibition
GABA
?
Girk2 Channel
Increased Inhibition
NTF Signaling
Neurodegeneration
Pathology of AD in DS
Increased App Gene Dose is Necessary for Decreased Endosomal Tranport and for Degeneration of BFCNs
Axonal transport
Neurodegeneration
APP and its Products - Finding the Culprit APP APP -CTF -CTF AICD A A A 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
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
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
Newly Discovered Modulators of -Secretase Impact A Peptide Production: Shorter Peptides/ Less Toxicity
Increased Inhibition
3 Targets NTF Signaling 4 Targets
The Investigators
Pavel Alexander
Ahmad Mike
Chengbiao
Steve
Rachel
April
Acknowledgements
Supported by: -Down Syndrome Research and Treatment Foundation -National Institutes of Health -Larry L Hillblom Foundation -Thrasher Foundation -Alzheimers Association -Cure Alzheimers Fund