Alzheimer's Disease Research
Maya Koronyo-Hamaoui, Ph.D.
Cedars-Sinai Medical Center
Los Angeles, CA
Title: Therapeutic Roles of ACE-overexpressing Monocytes in AD
Non-Technical Title: Delivery of ACE by Immune Cells to Reduce Aβ Pathology for AD Treatment
David B. Teplow, University of California, Los Angeles
Duration: July 1, 2013 - June 30, 2016
Award Type: Standard
Award Amount: $250,000
The incidence of Alzheimer’s disease (AD) is increasing dramatically, and yet no effective therapies exist to treat this devastating and invariably fatal disease. The most important goal of this study is to uncover new, unexplored therapeutic mechanisms of protection to brain cells by certain immune cells. Dr. Koronyo-Hamaoui’s research is being done in mouse models of AD. Specifically, the team will investigate a population of white blood cells (immune cells) that have been genetically engineered to overexpress an enzyme, called ACE, which can destroy a toxic protein associated with Alzheimer’s disease (beta-amyloid). Together with Dr. Teplow’s group, they will determine if the enzyme can help the cells to become more effective in eradicating and resisting highly damaging forms of beta-amyloid. Overall, the main focus of this project is to investigate the therapeutic potential of reducing the highly destructive form of beta-amyloid using genetically-modified immune cells.
Previously, Dr. Koronyo-Hamaoui has demonstrated a remarkable reduction of Alzheimer’s disease (AD) beta-amyloid and a restoration of cognitive function in mouse AD models that were genetically modified to overexpress the enzyme, called ACE, in specific immune cells. ACE protein is often associated with controlling blood pressure, but it is also known to degrade toxic beta-amyloid. Accumulation of toxic beta-amyloid assemblies in the brain is strongly linked to progression of AD. In this project, Drs. Koronyo-Hamaoui and Teplow are investigating whether high amounts of ACE expressed by certain white blood (immune) cells facilitate the degradation of toxic forms of beta-amyloid, after being selectively delivered to the brain by these cells. More importantly, the team seeks to determine whether high ACE also alters the ability of these immune cells to combat the progression of AD. In summary, they plan to selectively increase the expression of ACE, a beta-amyloid-destroying enzyme, in inflammatory cells that naturally migrate to the brain and support various tissue-healing processes.
Specifically, in the first two years, they will investigate the survival and protective activity of ACE-overexpressing immune cells in coping with pathological forms of beta-amyloid associated with AD, using cells cultured in a dish. For the second and third years, they will determine the therapeutic effects of a blood transfusion of ACE-modified immune cells into the mouse AD models, to see if this will help to prevent the harmful effects of beta-amyloid.
Once this study is completed, Drs. Koronyo-Hamaoui and Teplow expect to have identified and clarified the role of specific immune cells in clearing highly toxic forms of beta-amyloid and the role of ACE in controlling Alzheimer’s progression. The selective delivery of ACE by immune cells will reduce the risk of side effects, as the expression of ACE will be restricted to the lesion sites. Targeted ACE expression in the brain by inflammatory cells may be beneficial to reduce the burden of AD, and would question the merits of a life-long regimen of ACE inhibition or anti-inflammatory drugs.
In conclusion, this proposal may contribute to the understanding of human health in two ways: increased caution in the use of ACE inhibitors and anti-inflammatory drugs; and discovery of a novel AD immunotherapy to deliver ACE by immune cells migrating to the sites of AD brain lesions.
Maya Koronyo-Hamaoui, Ph.D., Assistant Professor in the Department of Neurosurgery and the Department of Biomedical Sciences at Cedars Sinai Medical Center, is head of the Neuroimmunology and Retinal Imaging Laboratory in the Department of Neurosurgery. She has held research positions at the Danek Gertner Institute of Human Genetics at The Chaim Sheba Medical Center at Tel Hashomer and was a faculty adjunct lecturer at The Sackler School of Medicine at Tel Aviv University, in Israel. She earned her bachelor’s degree cum laude and her master’s magna cum laude at Tel Aviv University before receiving her Ph.D. in human molecular genetics and psychiatric genetics at the university’s Sackler School of Medicine. She completed her postdoctoral fellowship in neuroimmunology at one of the world’s leading neuroimmunology laboratories at the Weizmann Institute of Science, Rehovot. Dr. Koronyo-Hamaoui’s laboratory focuses on various models of acute and chronic CNS-degeneration, with a great emphasis on Alzheimer’s disease: retinal pathology, retinal imaging and immune-based therapies. Her pioneering work on imaging of beta-amyloid retinal pathology created the basis for translating this novel approach to the clinic for early detection of Alzheimer’s disease through a non-invasive eye scanning; her team is committed to developing a definitive diagnosis early, when the disease is most likely to be treatable. Her other main focus is on immune-based mechanisms of repair and regeneration in the brain and developing immune-modulation therapies for Alzheimer's disease. In addition to the BrightFocus award, she has received the George S. Wise Faculty of Life Sciences recognition, the Wolf Fund and Sackler School of Medicine Faculty Dean's Honor & Prize for Best Achievements, a Pioneer in Medicine Award from the Brain Mapping Foundation, and the primary research award from the Coins for Alzheimer’s Research Trust (CART) Fund.