Study identifies promising new target for treating Alzheimer's disease

A class of proteins that control cell repair and enhance cell growth signaling systems may be a promising new target in the treatment of Alzheimer's disease and other neurodegenerative diseases, according to a new study led by researchers at Pennsylvania State University. The researchers found that inhibiting necessary glycosylation of these proteins promoted cell repair and reversed the cellular abnormalities that occur in neurodegenerative diseases.

The study was published in the journal Neurology today (July 2nd). iScienceThe researchers hold patents related to this work.

Until now, treatment strategies for Alzheimer's disease have focused primarily on pathological changes that are evident in the late stages of the disease. [U.S. Food and Drug Administration]Approved drugs have shown the ability to slightly slow disease progression by targeting one of these changes, amyloid accumulation. Drugs that act on the earliest cellular damage could be important tools to halt or reverse disease progression. We are interested in understanding the earliest cellular changes that are common not only to Alzheimer's disease but also other neurodegenerative diseases such as Parkinson's disease and amyotrophic lateral sclerosis (ALS).”

Scott Selleck, a professor of biochemistry and molecular biology in Penn State's Eberly College of Science and leader of the research team.

According to the Alzheimer's Association, approximately 6.9 million Americans aged 65 or older are estimated to have Alzheimer's disease. Despite its widespread impact, there is no consensus on the biological causes or mechanisms of the disease. Cell signaling molecules called heparan sulfate-modifying proteins are thought to be involved in the development of Alzheimer's disease, but their specific role is unknown, Selleck said. In this study, the team first performed a series of analyses in human cell lines and mouse brain cells that display hallmarks of Alzheimer's disease, showing that these proteins control cellular processes known to be affected in several neurodegenerative diseases.

Heparan sulfate-modified proteins are found both on the surface of animal cells and in the matrix between cells. This class of proteins is named after a sugar polymer with many sulfate groups called heparan sulfate. Heparan sulfate chains are attached to certain proteins, and this modification allows these proteins to assemble signaling complexes that affect cell growth and the way cells interact with their environment. These signaling pathways also control autophagy, a cellular repair process that removes damaged or dysfunctional components within the cell.

“In the early stages of several neurodegenerative diseases, autophagy is impaired, reducing the cells' ability to repair themselves,” said Selleck. “In this study, we found that heparan sulfate-modified proteins suppress autophagy-dependent cell repair. Furthermore, we show that compromising the structure and function of the glycosylation of these proteins increases the levels of autophagy, enabling cells to process damage.”

The researchers found that reducing the function of heparan sulfate-modifying proteins improved other early symptoms of neurodegenerative diseases in human and mouse cells, improved the function of mitochondria, which are responsible for producing energy in cells, and reduced the accumulation of lipids, or fatty compounds, in cells.

The researchers next evaluated the role of heparan sulfate-modifying proteins in an animal model of Alzheimer's disease: Drosophila lacking the presenilin protein. Mutations in presenilin cause early onset of the disease in humans, as they do in Drosophila. Defective presenilin leads to cell death and brain degeneration. In Drosophila lacking presenilin, reduced function of heparan sulfate chains prevented neuronal death and corrected other cellular defects. These results are directly relevant to recent human genetic studies, the researchers say.

“People with mutations in the presenilin gene PSEN1 develop Alzheimer's disease in their mid-40s. But if they also inherit a rare genetic change in a specific protein called APOE, onset can be delayed by decades,” Selleck said, explaining that APOE plays a key role in lipid transport and binds to heparan sulfate. “This change in APOE, which has been in the news lately, significantly reduces APOE's binding to heparan sulfate. Our study builds on these findings and suggests that heparan sulfate is directly involved in Alzheimer's pathology, which involves both PSEN1 and APOE. Targeting the enzyme that makes heparan sulfate may provide a means to halt neurodegeneration in humans.”

Collectively, these results indicate that disrupting the structure of heparan sulfate modifications prevents or reverses early cellular damage in these models of Alzheimer's disease.

“We were able to rescue the animals from neuronal loss, mitochondrial defects, and rescue behavioral deficits that are a measure of nervous system function,” Selleck said. “These findings suggest promising targets for future therapies that could rescue the earliest abnormalities that occur in many neurodegenerative diseases.”

The researchers also investigated how gene expression changed when they eliminated human cells' ability to make heparan sulfate chains. They found that the expression levels of more than 50% of nearly 70 genes known to be associated with late-onset Alzheimer's disease, including APOE, were modulated, suggesting a link between heparan sulfate-modifying proteins and a more common, later-onset form of Alzheimer's disease.

“It is crucial to target the cellular changes that occur earliest in disease progression and develop therapies that can halt or reverse them,” said Selleck. “We have demonstrated that common alterations in neurodegenerative diseases, such as reduced autophagy, mitochondrial defects, and lipid accumulation, can be halted by altering a type of heparan sulfate-modified protein. We believe that these molecules represent promising targets for drug development.”

The researchers believe that inhibiting this pathway and promoting cellular repair systems may be important for a variety of other diseases in which defective autophagy occurs.

“Manipulating this pathway could have broad applications in a variety of human disease conditions,” Selleck said.

Penn State's research team includes doctoral student Nicholas Schultheis and research assistant Alyssa Connell in the Biochemistry, Microbiology and Molecular Biology program, as well as undergraduate students Richard Mueller, Alexander Kapral, Robert Becker, Shalini Shah, Mackenzie O'Donnell, Matthew Roseman, Lindsay Swanson and Sophia Deguara as co-authors. University of Arizona researcher Weihua Wang and associate professor of pharmacology Fei Yin, and University of Georgia graduate student Tripti Saini and assistant professor of biochemistry and molecular biology Ryan Weiss also contributed to the study.

The research was funded by the National Institutes of Health and Penn State's Eberly College of Science.