Studying the Causes of Alzheimer’s Disease

In the United States today, more than five million people are affected by Alzheimer’s disease, a degenerative condition in which brain cells that are crucial to forming new memories die, severely impairing the cognitive abilities of patients.

Unfortunately, there are currently no treatments that prevent or slow the progression of this memory-robbing affliction. Researchers at the UW Medicine Institute for Stem Cell and Regenerative Medicine are determined to change that by taking a closer look at the factors that cause Alzheimer’s.

Studying the secrets of the brain, however, is uniquely challenging. For many diseases, cells can be obtained from a tissue sample—a biopsy—of the affected organ. But the brain is an especially delicate organ, making it difficult to extract live tissue.

One solution is to grow brain cells in the laboratory, which can be done in more than one way.

Researchers have the ability to convert skin – or other adult cells – into induced pluripotent stem cells, or iPSCs. These cells are called pluripotent stem cells because they have the potential to become many—pluri—different types of cells, including neurons that share the same genetic inheritance of the patient’s brain cells.

Another new technology allows researchers to directly convert a skin cell into a neuron. These new cells are called induced neurons or iNs. Like iPSC’s, this method maintains the genetic code written in the patient’s DNA.

But, iN’s also hold the memory of changes that occur to cells over a patient’s lifetime. These epigenetic changes are modifications to the way certain genes are expressed.  Diet, lifestyle, exposure to sunlight, and aging are all factors that can cause epigenetic changes.

Each of these technologies has unique advantages and disadvantages: iPSCs are infinitely renewable and are coaxed through a program that mimics natural neurodevelopment to make neurons in the lab. However this process may cause the cells to lose important epigenetic modifications. Directly induced neurons, iNs, maintain the epigenetics. The disadavantage: these modifications may be more similar to skin cells rather than brain cells.

This loss of epigentic changes is important because Alzheimer’s disease – like other degenerative diseases that impact the brain – is thought to be caused by a combination of genes we inherit and changes to those genes during our lifetimes that can increase or decrease our risk of developing a brain disorder.

So, controlling for environmental exposure helps researchers isolate the factors that may be causing Alzheimer’s onset.

Breakthrough Approaches to Brain Research

Now, in a major breakthrough, ISCRM researchers working with the UW Alzheimer’s Disease Research Center have created neurons from brain tissue – also known as leptomeninges – that are much more similar to brain cells in Alzheimer’s patients.

Because the leptomeninges are found so close to the brain, the neurons generated from this tissue are expected to be much more similar to the brain cells of these patients than would neurons generated from their skin cells.

“Leptomeningeal-derived neurons are ideal for the study of neurodegenerative disease”, said Jessica Young, Ph.D., an assistant professor in the UW Department of Pathology and a researcher at the Institute for Stem Cell and Regenerative Medicine. “They lie within the skull, immediately next to the brain, and are immersed in the same fluid that bathes the brain—the cerebral spinal fluid—and so are likely to share many of the same environmental exposures during life as have the nearby brain cells.”

Young led the study with C. Dirk Keene, M.D., Ph.D., Nancy and Buster Alford Endowed Chair in Neuropathology and associate professor, Department of Pathology, who is Leader of the UW Alzheimer’s Disease Research Center’s Neuropathology and Targeted Molecular Testing Core. The results of their study were published online in the Journal of Neuropathology & Experimental Neurology.

Stem Cell Lines: A Legacy of Community Participation

In the study, Young, Keene and their colleagues obtained brain tissue from patients with dementia shortly after death. All were volunteers in three studies in which patients are followed for many years, the Kaiser-Permanente Washington/ UW Adult Changes in Thought study, the Seattle Longitudinal Study, and the UW Alzheimer’s Disease Research Center study. Autopsies confirmed their brains had the classic changes seen with Alzheimer’s disease.

So far, thousands of individuals with and without dementia have enrolled in the community studies being conducted by UW and its partners. In some cases, volunteers have been followed for more than 30 years.  By donating brain tissue, these volunteers are leaving a legacy that may help researchers develop new ways to prevent and treat brain disorders.

Already the research team has used the tissue to create two types of cell lines. The first is a line of cells called pluripotent stem cells because they have the potential to become many—pluri—different types of cells, including neurons that share the same genetic inheritance of the patient’s brain cells. However, this type of stem cell  may lose many of the epigenetic modifications that might have occurred over a patient’s lifetime.

Researchers then created a second set of cells by converting the leptomeningeal cells into neurons directly without reverting them to the stem-cell state. Because these cells have not been reset, they are expected to have retained many of the epigenetic changes that are found in the adjacent brain cells that contributed to the patient’s neurodegenerative disease. “The epigenetic modifications will help tell us how certain epigenetic changes drive cells one way or the other,” Keene said.

Data to Drive New Discoveries

For Young and Keene, the long-term goal is to create a bank that will provide researchers from around the world access to the cell lines, a potential treasure trove of information about the factors that may lead to Alzheimer’s disease and other brain disorders.

“This bank of cell lines will help us to understand the basic cellular mechanics that contribute to the pathological changes seen in neurodegenerative disease and to test new compounds that might treat or prevent these disorders,” said Young.

This study was supported by University of Washington (UW) Alzheimer’s Disease Research Center (NIH AG005136), Kaiser Permanente Adult Changes in Thought Study (NIH AG006781), Morris K. Udall Center of Excellence for Parkinson’s Disease Research (NIH NS062684), the Nancy and Buster Alvord Endowment, the Tietze Foundation, and the Ellison Foundation.

Reference: Rose SE, Frankowski H, Knupp A, Berry BJ, Martinez R, Dinh SQ, Bruner LT, Willis SL, Crane PK, Larson EB, Grabowski T, Darvas M, Keene CD, Young JE. Leptomeninges-Derived Induced Pluripotent Stem Cells and Directly Converted Neurons From Autopsy Cases With Varying Neuropathologic Backgrounds. J Neuropathol Exp Neurol. 2018 Feb 21. doi: 10.1093/jnen/nly013. [Epub ahead of print]