Stem Cell Therapy in Alzheimer's Disease

Stem Cell Therapy in Alzheimer's Disease

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Description: What is a Stem Cell? Stem cells can make precise copies of themselves over and over again and stem cells can “differentiate” or mature into several cell types. What are Stem Cells? the raw material from which a body is built. Alzheimer Disease (AD): Could stem cells be used to replace the neurons that have been lost in AD? It is very unlikely that a cell-replacement approach could be developed to treat advanced AD.

For a Cell Replacement therapy you would need to: Make appropriate neural stem cells in vitro, Transplant cells that can survive and differentiate into multiple different types of mature neurons, Have the transplanted neurons extend axons and dendrites into appropriate target regions, Form appropriate synaptic connections.

 
Author: Mathew Blurton-Jones Ph.D. (Fellow) | Visits: 921 | Page Views: 1369
Domain:  Medicine Category: Therapy 
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Contents:
“New Hope: Stem Cell Therapy in
Alzheimer's Disease”
Mathew Blurton-Jones, Ph.D.
Department of Neurobiology & Behavior
Institute for Memory Impairments and Neurological Disorders
Sue and Bill Gross Stem Cell Research Center
University of California, Irvine

Outline


What are stem cells and what types of stem cells might be
used for Alzheimer’s disease research or therapies?



Examining the effects of Neural Stem Cell transplantation
in a transgenic mouse model of AD.



What are some of the key challenges to clinical translation?



How might induced pluripotent stem cell help us to
understand or treat AD?

What is a Stem Cell?

Stem cells can make precise copies of themselves over and over again
and stem cells can “differentiate” or mature into several cell types

What are Stem Cells?
the raw material from which a body is built

40+ years of life saving treatments

Alzheimer Disease (AD)
• Could stem cells be used to replace the neurons
that have been lost in AD?

It is very unlikely that a cell-replacement approach could be
developed to treat advanced AD

For a Cell Replacement therapy
you would need to:
1) Make appropriate neural stem cells in vitro

2) Transplant cells that can survive and differentiate into multiple
different types of mature neurons

3) Have the transplanted neurons extend axons and dendrites into
appropriate target regions.
4) Form appropriate synaptic connections

This is likely why so few studies have examined
Stem Cells transplantation for AD

Lund et al., 2011
Ann. Neurol. 70: 353-61

So why did we bother studying Stem Cell
Transplantation for AD?

Can Neural Stem Cell Transplantation
Affect Pathology or Cognition in
a Mouse Model of AD?

Mouse Neural Stem Cells (NSCs)
Neurons

Astrocytes

Oligodendrocytes

Why did we choose Green mice
instead of Red ones?

AD Neuropathology

• Amyloid Plaques: b-amyloid peptide (Ab)
• Neurofibrillary Tangles: hyperphosphorylated tau
• Neuronal and Synaptic loss: Ab oligomers

Synapse loss is the best correlate to dementia

Triple Transgenic Mice (3xTg-AD) Exhibit Age-Dependant
Accumulation of Plaques and Tangles

x

PS1 KI

PS1M146V
TAU P301L

APP Swe

Foster Mother

Transplantation of mNSCs into 18-month
old 3xTg-AD mice

3xTg-AD mice exhibit deficits in spatial memory
in the Morris Water Maze

Neural Stem Cells improve learning
in Aged AD Transgenic Mice
Acquisition

60

WT-NSC
WT-NSC
WT-NSC
WT-Vehicle
WT-Vehicle
3xTg-Vehicle
WT-Vehicle
3xTg-Vehicle
3xTg-NSC

Latency (sec)

50
40

*

30

*

*

5

6

20
10
0
1

2

3

4

Days
Blurton-Jones et al., PNAS, 2009

Neural Stem Cells
Improve Memory in Aged
AD Transgenic Mice

Blurton-Jones et al., PNAS, 2009

How does NSC transplantation
improve cognition in 3xTg-AD mice?

NSCs engraft into the host hippocampus

Subiculum

Dentate Gyrus

Green: GFP NSCs

Red: Aß plaques

Blurton-Jones et al., PNAS, 2009

Most NSCs differentiate into astrocytes
or oligodendrocytes

Blurton-Jones et al., PNAS, 2009

Only a small number of GFP+
neurons are detected
GFP

DCX

Merge

Blurton-Jones et al., PNAS, 2009

How does NSC transplantation
improve cognition in 3xTg-AD mice?
-Probably not by making new neurons

Do NSCs effect AD Pathology?

NSC transplantation has no effect on Aß pathology

Blurton-Jones et al., PNAS, 2009

NSC transplantation also has no effect on tau pathology

Blurton-Jones et al., PNAS, 2009

How does NSC transplantation
Improve Cognition in 3xTg-AD mice?
-not by altering AD pathology

Synapse loss is the best correlate to the
severity of dementia in AD
Synapses in a culture dish:
little red dots

Synapses in the brain:
1 quadrillion (1015) little red dots
Cell Bodies

Dendrites

Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R. 1991. Physical basis of cognitive alterations in Alzheimer's
disease: synapse loss is the major correlate of cognitive impairment. Annals of Neurology 30:572-580.

NSCs increase Synaptic Density
within the hippocampus
Vehicle

NSC

Blurton-Jones et al., PNAS, 2009

Neurotrophins are a group of proteins that
promote growth and synapse formation

Neurotrophin levels are decreased in AD and PD

NSCs elevate levels of Brain-Derived Neurotrophic
Factor (BDNF) within the brain

Blurton-Jones et al., PNAS, 2009

NSCs

BDNF

Synapses

Cognition

Is NSC-derived BDNF necessary
for improved memory?

Stable knockdown of BDNF in NSCs:

Repeat the Experiment:

BDNF-depleted NSCs
fail to improve cognition
and have a diminished
effect on synaptic density
Blurton-Jones et al., PNAS, 2009

NSCs

BDNF

Synapses

Cognition

Recent studies have now also found similar improvements in
cognition with Stem Cell Transplantation

Waldau et al., 2010 Aging & Disease 1:6-70

What are some of the key challenges
to clinical translation?
• Human NSCs
• Longer-term studies

Can we translate this towards a
clinical application?
• Requires clinical grade, GMP Human NSCs
• Requires testing human cells in AD mouse
models: Xenotransplantation

GMP-compliant Human Neural Stem Cells
• Cryopreserved cell banks
• Allogeneic, unmodified cell
Ø

No pre-differentiation

• Completed 2 Phase I Safety Studies
ØNeuronal Ceroid Lipofuscinosis
ØPelizaeus-Merzbacher Disease

• 2 ongoing Phase I/II Studies
ØSpinal Cord Injury
ØAge-Related Macular
Oct. 2012

Degeneration

Anderson et al., 2011
Regen Med 6:367-406

Can Transplantation of Human NSCs
improve memory in immunosuppressed
3xTg-AD mice?

All mice immunosuppressed with: rCTLA-Ig, anti-CD40L, anti-LFA-1

hNSCs improve Memory in
immunosuppressed 3xTg-AD mice

Control HuCNS-SC

Control HuCNS-SC

Both 3xTg-AD groups immunosuppressed with: rCTLA-Ig, anti-CD40L, anti-LFA-1

hNSCs improve Memory in
immunosuppressed 3xTg-AD mice

Control HuCNS-SC

Control HuCNS-SC

Both 3xTg-AD groups immunosuppressed with: rCTLA-Ig, anti-CD40L, anti-LFA-1

Engraftment of Human NSCs into
20-month old 3xTg-AD mice
Red: Human cytoplasm (SC121)

Nestin

Doublecortin

Doublecortin

immunosuppresion: anti-CD40L, rCTLA-Ig, anti-LFA-1

hGFAP

What are some of the key challenges
to clinical translation?
• Human NSCs

• Longer-term studies

How can we study long-term Human Stem cell
engraftment?

Lack T-cells, B-cells, and NK-Cells, yet have normal lifespans

- Highly aggressive plaque pathology
- Progressive Cell loss beginning at 9 months

Spleen flow cytometry confirms deletion of
B, T, and NK lineages in Rag-5x mice

With Jason Weinger and Tom Lane

Rag2ko/il2rgko-5xfAD mice develop
extensive Ab pathology and gliosis

Ab

Ab / GFAP

Sam Marsh

Ab / GFAP / Iba-1

6-months after transplantation HuCNS-SC have
survived and migrated extensively in 5x-Rag mice

STEM121 / Ab42

So is there a “Dark Side” to stem cell therapies?

Snake Oil salesman with beautiful websites and
miraculous promises have quickly jumped on the scene!

An unproven stem cell treatment in Russia caused
brain tumors in a young boy

Presence of cells with no Y chromosome in the Boy’s tumor

The International Society for Stem Cell Research has
created a campaign to inform people about the risks of
“Stem Cell Tourism”

http://www.closerlookatstemcells.org/

Are there any other ways that stem
cells could be used to understand
or treat AD?

2007

Shinya
Yamanaka

“Induced”

Patient skin cells

+ 4 key
genes

Can induced pluripotent stem cells (iPSC) be used to examine
the molecular mechanisms that cause late-onset AD?

AD Patient
Fibroblasts

Human iPS lines

Do multiple small genetic
differences add
up to shift the function or
phenotype of brain cells?

Late-onset AD is ~80% genetic

Once these key differences are identified, iPSCs could also be
used to screen for and test new drugs

The UCI Alzheimer’s disease research center has
begun generating a bank of patient-derived iPSCs
to ask these questions

UCI ADRC
skin or blood
sample

+ 4 genes

Tra160 stem cell marker

Summary


Neural stem cell transplantation improves cognition in a
mouse model of Alzheimer’s disease.



Understanding the mechanism by which NSCs influence
cognition could identify additional therapeutic approaches.



Translating findings toward the clinic will take some time
and we need to be cautious about unregulated ‘clinics’
promising stem cell cures.



Induced pluripotent stem cells could provide researchers
with a whole new way to study and understand what drives
AD and how we might treat it.

Acknowledgements
UC Irvine
Frank LaFerla
Rahasson Ager
Samuel Marsh
Joy Nerhus
Andy Agazaryan
Masashi Kitizawa
Kim Green
Wayne Poon
Thomas Lane
Jason Weinger
Wesley Chen
Natalie Sashkin Goldberg

UC San Diego
Eliezer Masliah
Brian Spencer

StemCells Inc.
Stephen Huhn
Alexandra Capela

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