Inheritance of an extra copy of the gene- β -amyloid precursor protein, APP, in individuals with Down syndrome leads to the inevitable development of early onset Alzheimer's disease, known to be linked to the deposition of Amyloid β peptide or Aβ in the brain. However, a new study published online by Proceedings of the National Academy of Sciences identifies βCTF, a small protein found in APP, as a novel factor for the development of Alzheimer's disease related endosome abnormalities, which have also been tied previously to the loss of brain cells in Alzheimer's disease.
"In the study, using the cells from individuals with Down syndrome that are genetically predisposed to developing Alzheimer's disease, we showed that elevated levels of βCTF, independent of Aβ, cause a specific pattern of endosome defects with similar pathology of brain cells in Alzheimer's disease," said Ying Jiang, PhD, lead author and clinical instructor in the Department of Psychiatry at NYU Langone Medical Center. "Our research was successfully able to pinpoint that βCTF causes Alzheimer's disease -related endosome defects and that we could successfully reverse these endosome defects by lowering βCTF levels in the cells."
Endosomes are membrane compartments in cells that support cell survival by absorbing outside nutrients and are crucial in neuronal functions. In Alzheimer's disease, endosome abnormalities are the earliest neuropathologic features to develop, appearing even earlier in cases where one of several major genetic risk factors for the disease in inherited. Endosomes are also suspected sites of Aβ production in the cells.
"In the field of Alzheimer's research, we have been questioning whether Aβ is the only target to better understand the progression of Alzheimer's disease and if lowering Aβ is the only hoped-for therapy," said Ralph Nixon, MD, PhD, professor, psychiatry and cell biology, director, NYU Center of Excellence on Brain Aging and the Silberstein Alzheimer's Institute at NYU Langone Medical Center. "This study demonstrates that an alternative protein factor, βCTF, derived from the gene APP, is also unequivocally involved in Alzheimer's disease and may be of additional importance for the development of future effective therapies."
Funding for this study was made possible through the National Institute on Aging (NIA) of the National Institutes of Health (NIH) The study was done in collaboration with NYU Langone Medical Center (NY, New York), the Center for Dementia Research at the Nathan Kline Institute (Orangeburg, NY); Mailman Research Center at McLean Hospital (Belmont, MA); Departments of Psychiatry and Neuropathology at Harvard Medical School (Boston, MA).
About NYU Langone Medical Center
NYU Langone Medical Center is one of the nation's premier centers of excellence in healthcare, biomedical research, and medical education. For over 168 years, NYU physicians and researchers have made countless contributions to the practice and science of health care. Today the Medical Center consists of NYU School of Medicine, including the Smilow Research Center, the Skirball Institute of Biomolecular Medicine, and the Sackler Institute of Graduate Biomedical Sciences; the three hospitals of NYU Hospitals Center, Tisch Hospital, a 705-bed acute-care general hospital, Rusk Institute of Rehabilitation Medicine, the first and largest facility of its kind, and NYU Hospital for Joint Diseases, a leader in musculoskeletal care; and such major programs as the NYU Cancer Institute, the NYU Child Study Center, and the Hassenfeld Children's Center for Cancer and Blood Disorders.
Journal
Proceedings of the National Academy of Sciences