Newswise — NEW YORK, NY (December 17, 2018)--Some neurons in the brain protect themselves from Alzheimer’s with a cellular cleaning system that sweeps away toxic proteins associated with the disease, according to a new study from Columbia University and the University of Cambridge.
The study, led by neuroscientist Karen Duff, PhD, of Columbia University Vagelos College of Physicians and Surgeons; Harry Fu, PhD, now at Ohio State University; and Michele Vendruscolo, PhD, of the University of Cambridge, was published online today in Nature Neuroscience.
Cells that Resist Alzheimer’s Clear Themselves of Toxic Tau Proteins
Early in the course of Alzheimer’s disease, neurons in the brain become clogged with toxic tau proteins that impair and eventually kill the neurons.
The new study found that more tau accumulates in certain types of neurons, because cellular systems that clear the proteins from the cells are predicted to be less effective in these neurons.
Researchers have long known that neurodegenerative diseases like Alzheimer’s affect some neurons but not others, even leaving neighboring neurons unharmed. But the reasons for this selectivity have been difficult to identify.
New Techniques Probed Inner Workings of Single Cells
The new study was only possible because of new techniques that allow researchers to probe individual cells in the brain.
When Duff and her colleagues examined data from single neurons in the human brain, they detected signs that the components of a cellular cleaning system were less abundant in the neurons that accumulate tau proteins.
To confirm the connection between the cleaning system and tau buildup, the researchers manipulated one of the components–a protein called BAG3–in mouse neurons. When the researchers decreased BAG3 levels in mouse neurons, tau piled up. But when BAG3 expression was enhanced, the neurons were able to rid themselves of excess tau.
The researchers have tantalizing, still unpublished data that the same housekeeping deficiencies found in vulnerable neurons occur with aging, which might explain the link between advanced age and Alzheimer’s disease.
“If we can develop therapies to support these natural defense mechanisms and stop tau from accumulating,” Duff says, “we might be able to prevent, or at least slow, the development of Alzheimer’s and other tau-related neurodegenerative diseases.”
About the Study
The study is titled “Selective vulnerability of excitatory neurons to tauopathy linked to tau homeostasis.”
Karen E. Duff, PhD, is professor of pathology & cell biology at Columbia University Vagelos College of Physicians and Surgeons and deputy director of the Taub Institute for Research on Alzheimer's Disease and the Aging Brainat Columbia University Irving Medical Center.
The other contributors are Andrea Possenti (University of Cambridge, Cambridge, UK), Rosie Freer (University of Cambridge), Yoshikazu Nakano (CUIMC), Nancy C. Hernandez Villegas (CUIMC), Maoping Tang (University of Rochester, Rochester, NY), Paula V. Cauhy (CUIMC), Benjamin A. Lassus (CUIMC), Shuo Chen (CUIMC), Stephanie L. Fowler (CUIMC), Helen Y. Figueroa (CUIMC), Edward D. Huey (CUIMC), and Gail V.W. Johnson (University of Rochester).
The study was supported by grants from the National Institutes of Health (AG056673, NS074874, and AG056151), the Alzheimer’s Association, the BrightFocus Foundation, the Tau Consortium, and the Cure Alzheimer’s Fund.
Karen Duff is a member of the board and science advisory board of Ceracuity LLC.
Columbia University Irving Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and 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 Vagelos 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. Columbia University Irving Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. For more information, visit cuimc.columbia.edu or columbiadoctors.org.
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Nature Neuroscience, December 17, 2018