The loss of short, day-to-day memories is often the first sign of Alzheimer’s – a disease that is expected, by the year 2050, to afflict 120 million people worldwide.
“People often joke that they must have Alzheimer’s because they can’t remember where they put their keys, but for a person with the disease, this type of short-term memory loss is extremely debilitating,” says the study’s lead author, Ottavio Arancio, Ph.D., associate professor of pathology and cell biology in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at Columbia University Medical Center.
Dr. Arancio says that the drug targets a previously unknown defect in the brains of mice with Alzheimer’s.
The reason why the drug improves memory lies in the way the brain records new memories. To create new memories, the neurons in the brain must manufacture new proteins. The first step is to open up and read the DNA, which contains instructions for making the proteins.
To read the DNA, the neuron attaches a chemical reactive group to the spool around which DNA is tightly wound. “These groups, called acetyls, unwind the DNA to make it more accessible,” says co-author Yitshak Francis, Ph.D., a postdoctoral research scientist at Columbia. “It’s like unwinding knitting wool from its spool.”
This unwrapping step, the researchers found, is impaired in mice with a form of Alzheimer’s disease. The mice with Alzheimer’s attached about half as many acetyls to DNA as normal mice and had poorer memory.
The researchers then discovered that they could improve memory in the Alzheimer’s-afflicted mice with a drug from a family of compounds now used to treat cancer, called HDAC inhibitors, which increase the DNA’s spool acetylation and gene transcription. The drug improved memory performance to the level found in normal mice.
“Because this type of drug has already been approved for some cancer patients,” says co-author Mauro Fà, Ph.D., associate research scientist in Columbia’s Taub Institute, “we hope that clinical trials for Alzheimer’s disease can start in about three to four years.”
“For making memories, you need transcription and protein synthesis at the cellular level. If you don’t have that, you don’t have memory,” said Dr. Francis.
This work was supported in part by Alzheimer Disease Research Zenith Award ZEN-07-58977, National Institutes of Health Grant R01 NS049442 (to O.A.) and by United Kingdom Alzheimer’s Research Trust Pilot Grant, The International Sephardic Educational Foundation (ISEF) Scholarship, The Lewis Family Trust Scholarship, The Sidney & Elizabeth Corob Charitable Trust Scholarship, the Charlotte and Yule Bogue Research Fellowships (to Y.I.F).
Authors of The Journal of Alzheimer’s Disease study include: Yitshak I Francis, Mauro Fà, Haider Ashraf, Hong Zhang, Agnieszka Staniszewski, David S. Latchman and Ottavio Arancio.
The Journal of Alzheimer’s Disease (http://www.j-alz.com) is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment and psychology of Alzheimer’s disease. The journal publishes research reports, reviews, short communications, book reviews, and letters-to-the-editor. Groundbreaking research that has appeared in the journal includes novel therapeutic targets, mechanisms of disease and clinical trial outcomes. The Journal of Alzheimer’s Disease has an Impact Factor of 5.101 according to Thomson Reuters’ 2008 Journal Citation Reports. The Journal is published by IOS Press (http://www.iospress.nl).
The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at Columbia University Medical Center is a multidisciplinary group that has forged links between researchers and clinicians to uncover the causes of Alzheimer’s, Parkinson’s and other age-related brain diseases and discover ways to prevent and cure these diseases. It has partnered with the Gertrude H. Sergievsky Center at Columbia University Medical Center which was established by an endowment in 1977 to focus on diseases of the nervous system. The Center integrates traditional epidemiology with genetic analysis and clinical investigation to explore all phases of diseases of the nervous system. For more information about these centers visit: http://www.cumc.columbia.edu/dept/taub/
Columbia University Medical Center provides international leadership in basic, pre-clinical and clinical research, in medical and health sciences education, and in patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Established in 1767, Columbia’s College of Physicians and Surgeons was the first institution in the country to grant the M.D. degree and is among the most selective medical schools in the country. Columbia University Medical Center is home to the largest medical research enterprise in New York City and state and one of the largest in the United States. For more information, please visit www.cumc.columbia.edu.