exploring the neurobiology of cognitive dysfunction in down syndrome william mobley m.d., ph.d. and...

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


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?



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 Gene(s)



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 Gene(s)



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.

exploring the neurobiology of cognitive dysfunction in down syndrome william mobley m.d., ph.d. and...

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