Blocking a Hormone That Acts on Brain Cells Limits Alzheimer’s Symptoms in Mice, Mount Sinai Researchers Discover
Mount Sinai researchers have learned from a study with mice that increased levels of a hormone produced by the pituitary gland that acts on brain cells could explain the disproportionate increase and severity of Alzheimer’s disease in post-menopausal women.
In the study, published in Nature, the Mount Sinai team, in collaboration with researchers from Emory School of Medicine, reported that blocking the action of follicle-stimulating hormone (FSH) on brain cells significantly reduced the debilitating effects of Alzheimer’s disease in mice, laying the foundation for a new drug therapy that might also impact osteoporosis and obesity.
“We are excited and cautiously optimistic that the molecule FSH may play an important role in Alzheimer’s disease, bone loss, and obesity simultaneously,” says senior author Mone Zaidi, MD, PhD, Director of the Center for Translational Medicine and Pharmacology and Professor of Medicine, and Pharmacological Sciences, at the Icahn School of Medicine at Mount Sinai. “Based on that finding, we have developed and hope to soon test a humanized monoclonal antibody that blocks FSH and could have enormous public health implications by potentially treating all three conditions.”
Few diseases have been more resistant to treatment than Alzheimer’s. The incidence of the crippling neurodegenerative disorder is particularly high among women after menopause, tracking closely with an increase in visceral adiposity (fat in the abdominal cavity), bone loss, and impaired energy balance. The Mount Sinai study, done collaboratively with senior author Keqiang Ye, PhD, from Emory, was designed to test whether high levels of FSH drive Alzheimer’s and, if so, whether blocking the hormone might prevent onset of the disease.
By conducting experiments in both labs, the researchers learned that FSH triggers features of Alzheimer’s disease in mouse models by acting on neuronal FSH receptors in the most vulnerable regions of the brain. Specifically, they found that FSH acts directly on the hippocampus and cortical neurons to accelerate deposition of the proteins amyloid-β and tau, the hallmarks of Alzheimer’s, and to impair cognition in mice displaying features of the disease. The teams also showed that blocking the activity of FSH with a highly targeted polyclonal antibody developed at Mount Sinai that binds to a short region of the FSH protein, or by reducing expression of the FSH receptor gene in the hippocampus, significantly reduces Alzheimer’s disease-like features in mice.
“We demonstrated that blocking FSH not only dampens Alzheimer’s disease pathology, but reduces bone loss and body fat in mouse models,” explain Dr. Zaidi, whose previous research on FSH’s effect on fat, published in Nature, was among the eight “notable advances” in biomedicine in 2017 named by Nature Medicine. “These results could provide the framework for development of a single FSH blocking agent to be used in humans for treating Alzheimer’s disease, obesity, and osteoporosis—conditions that affect millions of people worldwide.”
To that end, the Mount Sinai team recently published the development and characterization of a new humanized monoclonal antibody in the Proceedings of the National Academy of Sciences. “We have generated significant preclinical data by testing its efficacy and safety in animal models, and are greatly encouraged by the results, thanks to recent funding by the National Institute on Aging,” says Dr. Zaidi. He hopes to soon begin testing the antibody in early-stage clinical trials.
“This innovative study by Dr. Zaidi and colleagues exemplifies efforts at Mount Sinai based in bidirectional translational research. In this case, a novel discovery in patients with Alzheimer’s disease prompted studies in laboratory mice to understand underlying mechanisms and test possible approaches towards new therapies,” says Eric J. Nestler, MD, PhD, Nash Family Professor of Neuroscience, Director of The Friedman Brain Institute, and Dean for Academic Affairs of Icahn Mount Sinai, and Chief Scientific Officer of the Mount Sinai Health System. “The work now sets the stage for testing a fundamentally original way of treating Alzheimer’s disease.”
In addition to helping scientists better understand the pathophysiology of Alzheimer’s disease, Dr. Zaidi believes his research has “reaffirmed our view that pituitary hormones such as FSH have ubiquitous body actions, some of which are yet to be characterized, and that other chronic diseases like high cholesterol levels could be the focus of future studies involving FSH.”
About the Mount Sinai Health System
The Mount Sinai Health System is New York City's largest academic medical system, encompassing eight hospitals, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai advances medicine and health through unrivaled education and translational research and discovery to deliver care that is the safest, highest-quality, most accessible and equitable, and the best value of any health system in the nation. The Health System includes approximately 7,300 primary and specialty care physicians; 13 joint-venture ambulatory surgery centers; more than 415 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and more than 30 affiliated community health centers. The Mount Sinai Hospital is ranked on U.S. News & World Report's "Honor Roll" of the top 20 U.S. hospitals and is top in the nation by specialty: No. 1 in Geriatrics and top 20 in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Neurology/Neurosurgery, Orthopedics, Pulmonology/Lung Surgery, Rehabilitation, and Urology. New York Eye and Ear Infirmary of Mount Sinai is ranked No. 12 in Ophthalmology. Mount Sinai Kravis Children's Hospital is ranked in U.S. News & World Report’s “Best Children’s Hospitals” among the country’s best in four out of 10 pediatric specialties. The Icahn School of Medicine is one of three medical schools that have earned distinction by multiple indicators: ranked in the top 20 by U.S. News & World Report's "Best Medical Schools," aligned with a U.S. News & World Report "Honor Roll" Hospital, and No. 14 in the nation for National Institutes of Health funding. Newsweek’s “The World’s Best Smart Hospitals” ranks The Mount Sinai Hospital as No. 1 in New York and in the top five globally, and Mount Sinai Morningside in the top 20 globally.