exploring the neurobiology of cognitive dysfunction in down syndrome william mobley m.d., ph.d. and...
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Exploring the Neurobiology of Cognitive Dysfunction
in Down Syndrome
William Mobley M.D., Ph.D.and
Craig Garner Ph.D.
Stanford UniversityCenter for Research and Treatment of
Down Syndrome
The Center for Research and Treatment of Down Syndrome
Helping People with Down Syndrome Live More Independent Lives
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.
• 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
Small Change in Cognitive
Capability could have Profound impact on Independence
%Population
Independent LivingDependent Living
15%
Attack from several directions
15% Cognitive Improvement
Sleep CBTBrain
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
Federal researchdollars
per patient
0
350
700
Alzheimer’s Autism DownSyndrome
ALS
Down Syndrome – Important Facts
The Investment in Research is Tiny in Comparison to other Disorders
Neurons
Cognition
Neuronalsystems
Genes
Development
• Clinical trials • Industry
Delivery
• Health Care
Neuroscience
Translating Research Advances in DS
NIH Doesn’t Push: Industry Doesn’t Pull
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.
Neurons
Cognition
Neuronalsystems
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
Stanford UniversityDirector: William MobleyCo-Director: Craig Garner
Principle Investigators: Robert Malenka, CraigGarner, Irving Weissman, Barbara Sommer, AllanReiss, Dan Madison, Emmanuel Mignot,William Mobley
Associate Investigators: Pavel Belichenko, AlexanderKleschevnikov, Jean Delcroix, Ahmad Salehi, Subha Basu, Ke Zhan, Chengbiao Wu, Damien Colas,Fabian Fernandez, Martina Blank
DS Center Participants
UCSFCharles EpsteinAngela Villar
UC BerkeleyLucia Jacobs
Case WesternBruce Lamb
Med Univ SCKumar Sambamurti
NYURandy Nixon
Johns HopkinsRoger Reeves
UT SouthwesternLuis Parada
UCSDEliezer MasliahLarry GoldsteinGorazd Stokin
HarvardWeiming Xia
UNDERSTANDING AND TREATING DOWN SYNDROME
-NOT TOO COMPLEXBecause specific genes and mechanisms will be found to cause cognitive problems
-NOT TOO DIFFICULTBecause tools are available to find these genes and understand how an extra copy causes cognitive problems
-NOT TOO LATEBecause brain function can be modified, even in adults
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
presynapse
postsynapse
NEURONAL CIRCUITS ARE DISRUPTED IN DS
x x
DISRUPTED
X X
A) Normal neonatal brain B) Down syndrome (DS; trisomy 21) (from Marin-Padilla, 1976).
Synapse Structure is Abnormal in Individuals with Down Syndrome
10m10m
A B
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.
APPGrik1
Sod1
Gart
Sim2Dryk1a
Ets2Mx1
Sod1
Gart
Sim2Dryk1a
Mx1Ets2
APPGrik1Sod1
Ts65Dn Ts1Cje Ms1Ts65
A Mouse Model of Down Syndrome
Gabpa
These Mice Carry an Extra Copy of Many of the Genes Responsible For Down Syndrome
PP
Sch
MF
CA1
Alv
CA3
EntorhinalCortex
12
3
Cortex
Anatomy of Circuits in the Hippocampus: a Brain RegionCritical for Learning and Memory
Dentate Gyrus Cholinergic Neuron
DGC
Perforant Path
Mossy cell
Mossy cell
GABAergic neuron
GABAergic neuron
GLGL
IMLIML
OMLOML
MMLMML
Cholinergic neuron
Cholinergic neuron
DGC
PPPP
Synaptic Structure and Function are Abnormal in Ts65Dn Mice
Synaptic Structure and Function are Abnormal in Ts65Dn Mice
2N mice2N mice
GluGlu
GABA
GABA
AChACh
Ts65Dn miceTs65Dn mice
AChACh
GluGlu
GABAGABA
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?
Synaptic Structure and Function are Abnormal in Ts65Dn Mice
Synaptic Structure and Function are Abnormal in Ts65Dn Mice
2N mice2N mice
GluGlu
GABA
GABA
AChACh
Ts65Dn miceTs65Dn mice
AChACh
GluGlu
GABAGABA
Dentate Gyrus
CA3
CA1 MFPP
Inhibitory neuron
Synaptic Plasticity Was Suppressedin Ts65Dn Mice
Synaptic Plasticity was Restoredby Blocking Inhibition
Synapses Become More Efficient During Learning – Synaptic Plasticity
Abnormal Synaptic Function in Ts65Dn Mice
Proposed Mechanism for Decreased Synaptic Plasticity in Ts65Dn
Increased inhibition
Suppression of Learning
Decreased Synaptic Plasticity
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
Mossy cellMossy cellGABA-ergic
cellGABA-ergic
cell
GLGL
IMLIML
PPPP
OMLOML
MMLMML
Cholinergic neuron
Cholinergic neuron
DGC
NTF NTF
NEURONAL CIRCUITS ARE DISRUPTED IN DS
x x
DISRUPTED
XXNTFNTF
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
2N Ts65Dn
Amount of NGFTransported
125I-NGF
Cholinergic Neurons
Hippocampus
Reduced Axonal Transport of NGF from the Hippocampus to Cholinergic Neurons in Ts65Dn
Candidate Genes for Failed NGF Retrograde Transport
GABPA
AppADAMTS1
ADAMTS5
PRED28
ZNF294
C21orf6
USP16
CCT8
GRIK1
CLDN17
CLDN8
TIAM1
SOD1
T
APPGrik1
Sod1
Gart
Sim2Dryk1a
Ets2Mx1
Ts65Dn
Gabpa
Ts65Dn: APP+/+/+
Ts65Dn: APP+/+/- 2N
Per
cen
t
Cell profile area (m2)0 50 100 150 200 250 3000
10
20
30
40
50
60
0
20
40
60
80
100
NG
F T
ran
spor
t (p
erce
nt
of 2
N)
*
**
2NTs65Dn/APP++-
Ts65Dn/APP+++
Ts65Dn/APP++-Ts65Dn/APP+++
Deleting One Copy of App in Ts65Dn Mice Markedly Enhances 125I-NGF Transport and
Prevents BFCN Atrophy
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
A Proposal for Pathogenesis
Increased APP Gene Expression
Cholinergic Neuron Dysfunction and Degeneration
Decreased NGF Transport
A Proposal for Pathogenesis
Increased APP Gene Expression
No Cholinergic Neuron Dysfunction and Degeneration
Normal NGF Transport
Treatment
Summary1) 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.
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