Alzheimers Neurons Created from Pluripotent Stem Cells

First-ever feat provides new method to understand cause of
disease, develop drugs

Newswise — Led by researchers at the University of California,
San Diego School of Medicine, scientists have, for the first
time, created stem cell-derived, in vitro models of sporadic
and hereditary Alzheimer’s disease (AD), using induced
pluripotent stem cells from patients with the much-dreaded
neurodegenerative disorder.

“Creating highly purified and functional human Alzheimer’s
neurons in a dish – this has never been done before,” said
senior study author Lawrence Goldstein, PhD, professor in the
Department of Cellular and Molecular Medicine, Howard Hughes
Medical Institute Investigator and director of the UC San Diego
Stem Cell Program. “It’s a first step. These aren’t perfect
models. They’re proof of concept. But now we know how to make
them. It requires extraordinary care and diligence, really
rigorous quality controls to induce consistent behavior, but we
can do it.”

The feat, published in the January 25 online edition of the
journal Nature, represents a new and much-needed method
for studying the causes of AD, a progressive dementia that
afflicts approximately 5.4 million Americans. More importantly,
the living cells provide an unprecedented tool for developing
and testing drugs to treat the disorder.

“We’re dealing with the human brain. You can’t just do a biopsy
on living patients,” said Goldstein. “Instead, researchers have
had to work around, mimicking some aspects of the disease in
non-neuronal human cells or using limited animal models.
Neither approach is really satisfactory.”

Goldstein and colleagues extracted primary fibroblasts from
skin tissues taken from two patients with familial AD (a rare,
early-onset form of the disease associated with a genetic
predisposition), two patients with sporadic AD (the common form
whose cause is not known) and two persons with no known
neurological problems. They reprogrammed the fibroblasts into
induced pluripotent stem cells (iPSCs) that then differentiated
into working neurons.

The iPSC-derived neurons from the Alzheimer’s patients
exhibited normal electrophysiological activity, formed
functional synaptic contacts and, critically, displayed
tell-tale indicators of AD. Specifically, they possessed
higher-than-normal levels of proteins associated with the
disorder.

With the in vitro Alzheimer’s neurons, scientists can more
deeply investigate how AD begins and chart the biochemical
processes that eventually destroy brain cells associated with
elemental cognitive functions like memory. Currently, AD
research depends heavily upon studies of post-mortem tissues,
long after the damage has been done.

“The differences between a healthy neuron and an Alzheimer’s
neuron are subtle,” said Goldstein. “It basically comes down to
low-level mischief accumulating over a very long time, with
catastrophic results.”

The researchers have already produced some surprising findings.
“In this work, we show that one of the early changes in
Alzheimer’s neurons thought to be an initiating event in the
course of the disease turns out not to be that significant,”
Goldstein said, adding that they discovered a different early
event plays a bigger role.

The scientists also found that neurons derived from one of the
two patients with sporadic AD exhibited biochemical changes
possibly linked to the disease. The discovery suggests that
there may be sub-categories of the disorder and that, in the
future, potential therapies might be targeted to specific
groups of AD patients.

Though just a beginning, Goldstein emphasized the iPSC-derived
Alzheimer’s neurons present a huge opportunity in a desperate
fight. “At the end of the day, we need to use cells like these
to better understand Alzheimer’s and find drugs to treat it. We
need to do everything we can because the cost of this disease
is just too heavy and horrible to contemplate. Without
solutions, it will bankrupt us – emotionally and financially.”

Funding for this research came, in part, from the California
Institute for Regenerative Medicine, the Weatherstone
Foundation, the National Institutes of Health, the Hartwell
Foundation, the Lookout Fund and the McDonnell Foundation.

A patent application has been filed on this technology by the
University of California, San Diego. For more information, go
to: http://techtransfer.universityofcalifornia.edu/NCD/22199.html^[1]

Co-authors are Mason A. Israel and Sol M. Reyna, Howard Hughes
Medical Institute and UCSD Department of Cellular and Molecular
Medicine and UCSD Biomedical Sciences Graduate Program; Shauna
H. Yuan, Howard Hughes Medical Institute and UCSD Department of
Cellular and Molecular Medicine and UCSD Department of
Neurosciences; Cedric Bardy and Yangling Mu, The Salk Institute
for Biological Studies; Cheryl Herrera, Howard Hughes Medical
Institute and UCSD Department of Cellular and Molecular
Medicine; Michael P. Hefferan, UCSD Department of
Anesthesiology; Sebastiaan Van Gorp, Department of
Anesthesiology, Maastricht University Medical Center,
Netherlands; Kristopher L. Nazor, Department of Chemical
Physiology, The Scripps Research Institute; Francesca S.
Boscolo and Louise C. Laurent, UCSD Department of Reproductive
Medicine; Christian T. Carson, BD Biosciences; Martin Marsala,
UCSD Department of Anesthesiology and Institute of
Neurobiology, Slovak Academy of Sciences, Slovakia; Fred H.
Gage, The Salk Institute of Biological Studies; Anne M. Remes,
Department of Clinical Medicine, Neurology and Clinical
Research Center, University of Oulu, Finland; and Edward H.
Koo, UCSD Department of Neurosciences.

About Alzheimer’s disease
An estimated 5.4 million Americans have Alzheimer’s disease,
according to the Alzheimer’s Association. Two-thirds are women.
By 2050, as many as 16 million Americans are projected to have
the disease. In 2011, the economic cost of caring for
Alzheimer’s patients exceeded $183 billion, projected to rise
to $1.1 trillion by 2050. Alzheimer’s is the sixth leading
cause of death in the United States, killing more than 75,000
Americans annually. Currently, there are no drugs to prevent,
alter or cure the disease.

Video: To watch or download video of Goldstein explaining the
challenges of Alzheimer’s disease research and the findings of
this Nature paper, go to http://vmg.ucsd.edu/download/Media%20Release%20Footage/^[2] and click
on
“L.Goldstein-StemCellDerivedNeurons.”

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References

1. ^{^} http://techtransfer.universityofcalifornia.edu/NCD/22199.html
   (techtransfer.universityofcalifornia.edu)
2. ^{^} http://vmg.ucsd.edu/download/Media%20Release%20Footage/
   (vmg.ucsd.edu)