Research Focuses on Neuron Survival

Work could profoundly alter treatment for Alzheimer’s and Parkinson’s patients

UH Innovations in Neurology & Neurosurgery – Fall 2018

 Andrew Pieper, MD, PHD

When Andrew A. Pieper, MD, PhD, joined University Hospitals from the University of Iowa Carver College of Medicine in February, he brought with him exciting research into how to promote the survival of nerve cells. This work has the potential to profoundly alter treatment options for patients suffering from conditions such as Alzheimer’s or Parkinson’s disease, traumatic brain injury, mental illnesses such as depression and schizophrenia, and more.

Since current treatments for most neurodegenerative diseases today only address symptoms, making significant improvements in the care for patients with these conditions requires identifying neuroprotective compounds that can slow or stop nerve cell death, Dr. Pieper says.

He explains that it has been known for some time that patients with Alzheimer’s disease have buildups of amyloid plaques and neurofibrillary tangles of abnormal tau protein, but it is not known whether these accumulations are the cause or the effect in the process. Moreover, therapeutic strategies targeting these factors have failed to help patients with Alzheimer’s disease in clinical trials. Dr. Pieper’s research has shown that keeping neurons alive allows the brain to continue to function properly either way.

“Protecting neurons may be enough to help these patients continue to live healthy, productive lives, without targeting amyloid plaques in the brain,” he says.

KEEPING BRAIN CELLS ALIVE

Dr. Pieper’s past work in this area involved using an experimental compound named P7C3-S243 to keep brain cells alive in a rat model of Alzheimer’s disease. He discovered the P7C3 family of compounds more than a decade ago, and P7C3 compounds have since been used to protect new and mature neurons in animal models of a wide range of neurodegenerative conditions, including Parkinson’s, amytrophic lateral sclerosis, stroke and traumatic brain injury. Compounds derived from P7C3 have also shown success in protecting animals from developing depression-like behavior in response to stress-induced death of nerve cells in the hippocampus.

“The hippocampus is critical to cognition and mood regulation,” Dr Pieper says, “and protecting this region could help patients with a wide variety of neuropsychiatric conditions, including depression.”

When the compound was tested in a rat model of Alzheimer’s disease, the researchers noted that prior to developing learning and memory problems similar to what humans experience, the rats started to show depression-like symptoms. Although developing such symptoms late in life is known to be associated with an increased risk of Alzheimer’s in humans, it previously had not been seen in animal models.

The researchers built on this observation to monitor the development of these symptoms in Alzheimer’s model rats, as well as wild type rats receiving the P7C3 compound or a placebo for upward of two years. They were able to show that the Alzheimer-model animals that received the compound did not exhibit depressive behavior and maintained better cognitive abilities as they aged than their untreated peers.

Post-mortem analysis found that the compound did not impact amyloid plaques, tau tangles or neuroinflammation in the brains of Alzheimer-model rats, but did achieve a much higher rate of neuron survival in these animals – all the way through advanced stages of the disease.

“This suggests that specifically keeping nerve cells alive in the brain without changing other events in Alzheimer’s disease, such as amyloid accumulation, tau tangles or neuroinflammation, might help patients,” Dr. Pieper says. “In cases of new-onset, late-life depression often associated with the early stages of Alzheimer’s disease, this treatment might be particularly useful, as it could help both stabilize mood and protect patients from memory impairment.”

LOOKING AHEAD

With expertise and training in both psychiatry and neurosciences, Dr. Pieper’s work at UH will focus on leading the Cleveland Brain Health Initiative, a multidisciplinary citywide effort with substantial grants from the Mount Sinai Foundation and the Cleveland Foundation that began about seven years ago. All of the Cleveland hospitals are involved. University Hospitals, Cleveland Clinic and Case Western Reserve School of Medicine are the anchors.

Dr. Pieper is also Director of Neurotherapeutic Discovery at the Harrington Discovery Institute, where he will be coordinating worldwide efforts to support translation of academic discoveries into new treatments for patients.

You can contact Dr. Pieper regarding research initiatives at Andrew.Pieper@UHhosptials.org.