To date, no medications or lifestyle changes have been shown to reverse Alzheimer’s disease. But new research from a team at the University of Nebraska Medical Center (UNMC) describes a new cellular therapy that protected damaged brain cells and restored brain homeostasis in a mouse model of Alzheimer’s disease. Importantly, this treatment also improved learning and memory in these animals.
In the paper, published in the journal Molecular Neurodegeneration and titled “Amyloid-β Specific Regulatory T Cells Attenuate Alzheimer’s Disease Pathobiology in APP/PS1 Mice,” the UNMC group genetically modified a specific class of immune controlling cells (called regulatory T cells or Treg) to make them specifically react to a key protein known to be associated with Alzheimer’s disease. This protein, called amyloid-beta, “clumps together” in the brains of Alzheimer’s patients, forming plaques that disrupt nerve cell vitality. This leads to an inability of nerve cells to send signals and communicate with other nerve cells in and outside the brain. Over time, this eventually results in brain cell death, which in turn triggers the memory loss and behavioral abnormalities seen during progressive human disease.
In the study, the engineered Treg cells were administered to mice by injection into the blood stream. The study’s results showed that the cell treatment reduced amyloid plaque buildup and brain inflammation. Strikingly, the therapy also improved cognitive functions in diseased animals. The APP/PS1 Alzheimer’s mouse model was used as it exhibits amyloid plaque formation and cognitive impairment similar to those seen in human Alzheimer’s disease.
“The link between regulatory T cells, or ‘Treg,’ and the treatment of neurodegenerative diseases is well established,” said Howard E. Gendelman, MD, chair of the UNMC Department of Pharmacology and Experimental Neuroscience (PEN). “This work demonstrates the advantages of antigen specificity for the Tregs. The approach promoted improved therapeutic activities of Treg in Alzheimer’s disease models and more specifically changed some features of the disease course to near normal levels observed in models without the disease.
“No one has yet shown clear pathological and cognitive improvements with therapy,” said Lee Mosley, PhD, a professor and director of the neurodegenerative disease program in UNMC’s PEN department.
The novelty of this study lies in its approach of using the body’s immune system to fight against the key factors of Alzheimer’s, as well as using modified cells to improve their effect by directly targeting a key disease-associated protein. By genetically engineering these regulatory T cells to express a receptor that specifically recognizes the amyloid-β protein, these immune cells could provide a targeted and potentially more effective treatment strategy. These immune cells also would be able to reach the brain to impart their effects – which is a significant advantage because many other treatments have difficulty entering the brain due to the blood brain barrier.
Currently, antibody-based therapies that target the amyloid-beta protein are available. However, there can be adverse side effects related to the removal of amyloid from around the blood vessels that may limit who is eligible to receive such therapy. By minimizing the inflammatory response, it might be possible to decrease these side effects and increase the number of eligible patients.
“An imbalance between cytotoxic and neuroprotective classes of T cells may play a role in a whole host of central nervous system (CNS) disease states, which in turn promotes a vicious cycle of microglial activation, chronic neuroinflammation, and neuronal injury,” said William Daley, PhD, the program officer of the NINDS grant that supported this study. “And while previous work has shown that boosting neuroprotective Tregs can help improve this imbalance and break the chronic neuroinflammatory cycle, this current study takes this concept to a whole new level by demonstrating that neuroprotective Tregs can be specifically targeted to diseased areas of the brain with an engineered receptor.”
Avindra Nath, MD, senior investigator and clinical director for the NINDS intramural program, noted that “the study is an important development in the field that advances the possibility of using cell-based therapies for targeting protein aggregates in neurodegenerative diseases.”
Recent clinical trials have indeed shown potential benefit for the use of regulatory T cells as a treatment for Alzheimer’s disease and other neurodegenerative disorders both in animals and in humans with the disease, said Pravin Yeapuri, PhD, a UNMC postdoctoral fellow and a lead author in the study.
“But the limitation has been how to get protective regulatory cells into the regions of the brain most affected in Alzheimer’s disease,” Dr. Yeapuri said.
This work is a significant first step advance in Alzheimer’s research and the potential for a new therapy. While the research requires next step testing in humans to determine clinical disease efficacy, it remains a paradigm shift for the field of Alzheimer’s therapeutics, said Jatin Machhi, PhD, a former instructor in the UNMC pharmacology and experimental neuroscience department and lead study investigator.
UNMC Chancellor Jeffrey P. Gold, MD, congratulated Dr. Gendelman and the research team on the paper. “This is an exciting step forward,” Dr. Gold said of the research. “We are proud of the UNMC team’s work in this important area, which impacts so many. We look forward with great excitement to seeing where this important breakthrough may lead in the fight against Alzheimer’s.”
Stanley Appel, MD, the Edwards Distinguished Endowed Chair for ALS at Houston Methodist and director of the Johnson Center for Cellular Therapeutics, said: “The development of beta-amyloid-targeted Tregs and the beneficial effects of their infusion in AD-model mice are exciting accomplishments of the Gendelman team. This is clearly the beginning of a new chapter in immunomodulatory therapy for AD.”
Each of the other UNMC faculty, students, and technical co-investigators played pivotal roles in design, data collection, and interpretations in this study included Yaman Lu, Mai Mohamed Abdelmoaty, Rana Kadry, Milankumar Patel, Shaurav Bhattarai, Eugene Lu, Krista Namminga, Katherine Olson, PhD, Emma Foster.
The research was supported by by the National Institutes of Health Grants P01 DA028555, R01 NS36126, P01 NS31492, P01 MH64570, P01 NS43985, P30 MH062261, R01 AG043540, and 2R01 NS034239; the Frances and Louie Blumkin and Harriet Singer Research Foundations, the Carol Swarts, MD Emerging Neuroscience Research Laboratory; and the Margaret R. Larson Professorship. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.