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Stem Cell-Based Alzheimer's Model Called 'Significant Step' Toward New Therapies

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The work was presented July 19 at the Alzheimer's Association International Conference in Vancouver.

"Current animal models of Alzheimer's are highly engineered to express elements of the disease, and while valuable for research incompletely represent how the disease forms and progresses in people," said William Thies, Ph.D., the Alzheimer Association's chief medical officer. "In order to develop better therapies and eventually prevent Alzheimer's, we need better, more accurate animal and cellular models of the disease.

"This newly reported research is a significant step forward in that direction."

"Patient-derived Alzheimer's cells will prove invaluable for future research advances, as they already have with patient-derived ALS cells," Susan Solomon, NYSCF's CEO, added. "They will be a critical tool in the drug discovery process, as potential drugs could be tested directly on these cells."

Most of the current Alzheimer's mouse models incorporate genetic changes found in familial young-onset forms of Alzheimer's. However, the hallmark amyloid plaques found in the brains of people with Alzheimer's do not form in the same way as in the brains of mice and significant brain cell death does not occur.

That's what spurred Andrew Sproul, Ph.D., and his colleagues who work in the laboratory of Scott Noggle, Ph.D., the NYSCF-Charles Evans Senior Research Fellow for Alzheimer's disease, to take a new approach. They reprogrammed skin cells taken from 12 patients diagnosed with early-onset Alzheimer's and from healthy, genetically related individuals into induced pluripotent stem (iPS) cells. They then used the iPS cells, which can differentiate into any cell type, to create the cells affected in Alzheimer's. These brain cells — called cholinergic basal forebrain neurons — recapitulate the features and cellular-level functions of patients suffering from Alzheimer's.

"One advantage of this technology is that we get a near infinite supply of disease and control patient stem cells," said Sproul, a postdoctoral associate who presented the findings. "Another is that we can then turn the iPSCs into any tissue in the body.

"This allows us to investigate the role of various cells in Alzheimer's disease progression by manipulating the iPSCs to form different types of brain cells (forebrain nerve cells, neural stem cells, glial cells) that we and others believe are involved in Alzheimer's."

Four years ago, a NYSCF-funded team created a cell-based model for ALS. The cell-based model for Alzheimer's builds on this work. It already has led to important findings.

Preliminary results done in collaboration with Sam Gandy, M.D., Ph.D., an expert in the pathology of Alzheimer's at Mount Sinai School of Medicine, demonstrated differences in cellular function in Alzheimer's patients. Specifically, Alzheimer's neurons produce more of the toxic form of beta amyloid, the protein fragment that makes up amyloid plaques, than in disease-free neurons.

"iPS cell technology along with whole genome sequencing provide our best chance at unraveling the causes of common forms of Alzheimer's disease," Dr. Gandy said.

The research reported on at the conference focused on people with presenilin-1 mutations, which are behind the most common form of rare, inherited, young-onset Alzheimer's. However, because the overwhelming majority of people with Alzheimer's have the late-onset sporadic form of the disease, the scientists say they plan to expand their research to include large-scale production of iPSCs from people with different types of Alzheimer's.

Learn more:
Alzheimer's Association
New York Stem Cell Foundation (NYSCF)