A new target for the prevention of adverse immune responses identified as factors in the development of Alzheimer's disease (AD) has been discovered by researchers at the University of South Florida's Department of Psychiatry and the Center of Excellence for Aging and Brain Repair.
Their findings are published online in the Journal of Neuroscience (http://www.
The CD45 molecule is a receptor on the surface of the brain's microglia cells, cells that support the brain's neurons and also participate in brain immune responses.
Previous studies by the USF researchers showed that triggering CD45 was beneficial because it blocked a very early step in the development of Alzheimer's disease. In the present study, the researchers demonstrated in Alzheimer's mouse models that a loss of CD45 led to dramatically increased microglial inflammation.
Although the brain's immune response is involved in Alzheimer's disease pathology, "this finding suggests that CD45 on brain immune cells appears critically involved in dampening harmful inflammation," said study senior author Jun Tan, MD, PhD, a professor of psychiatry and Robert A. Silver chair at the Rashid Laboratory for Developmental Neurobiology, USF Silver Child Development Center and research biologist for Research and Development Service at the James A. Haley Veteran's Hospital.
The investigators also found an increase in harmful neurotoxins, such as A beta peptides, as well as neuron loss in the brains of the test mice.
"In short, CD45 deficiency leads to increased accumulation of neurotoxic A beta in the brains of old Alzheimer's mice, demonstrating the involvement of CD45 in clearing those toxins and protecting neurons," Dr. Tan said. "These findings are quite significant, because many in the field have long considered CD45 to be an indicator of harmful inflammation. So, researchers assumed that CD45 was part of the problem, not a potential protective factor."
The next step is to apply these findings to develop new Alzheimer's disease treatments, said Paula Bickford, PhD, a professor in the USF Department of Neurosurgery and senior career research scientist at the James A. Haley Veteran's Hospital.
"We are already working with Natura Therapeutics, Inc. to screen for natural compounds that will target CD45 activation in the brain's immune cells," Dr. Bickford said.
Other researchers involved in this study were: Dr. Yuyan Zhu, Dr. Huayan Hou, Dr. Kavon Rezai-zadeh, Dr. Brian Giunta, Ms. Amanda Ruscin, Dr. Carmelina Gemma, Dr. JingJi Jin, Dr. Natasa Dragicevic, Dr. Patrick Bradshaw, Dr. Suhail Rasool, Dr. Charles G. Glabe (University of California, Irvine, CA), Dr. Jared Ehrhart, Dr. Takashi Mori (Saitama Medical Center/Saitama Medical University, Japan), Dr. Demian Obregon, Dr. Terrence Town (Cedars-Sinai Medical Center, Los Angeles, CA). Drs. Yuyan Zhu and Huayan Hou contributed equally to this work.
Their work was supported by the National Institute on Aging and the National Institute of Neurological Disorders and Stroke, National Institutes of Health.
The mission of the Center of Excellence for Aging and Brain Repair is to develop new therapeutic strategies to promote repair and regeneration of aging and diseased brain. Building on a foundation of excellence in basic and clinical research, we focus on translating innovative ideas into industrial partnerships, educational and clinical services to address key needs of the community and those suffering from brain injury and disease.
USF Health (www.health.usf.edu) is dedicated to creating a model of health care based on understanding the full spectrum of health. It includes the University of South Florida's colleges of medicine, nursing, pharmacy and public health; the schools of biomedical sciences as well physical therapy & rehabilitation sciences; and the USF Physicians Group. With more than $394.1 million in research grants and contracts in FY2009/2010, the University of South Florida is one of the nation's top 63 public research universities and one of only 25 public research universities nationwide with very high research activity that is designated as community-engaged by the Carnegie Foundation for the Advancement of Teaching.