SAN DIEGO--(BUSINESS WIRE)--Physician-Scientists in the Neurodegenerative Disease Center at San Diego’s Scintillon Institute for Biomedical and Bioenergy Research discovered that high sugar caused by Type 2 (adult-onset) diabetes and the beta-amyloid protein associated with Alzheimer’s disease induce the same pathological modification on multiple enzymes in the brain. The findings are being heralded as a major development in explaining the well-known association between Type 2 diabetes and Alzheimer’s disease. The publication appeared in the January 8, 2016 online edition of Nature Communications.
The scientists used a so-called “disease-in-a-dish” model to discover molecular pathways that are in common in both diabetes and Alzheimer’s. Specifically, they genetically reprogrammed the skin of human patients to make induced pluripotent stem cells, which were then used to derive nerve cells. They also used mouse models of each disease to analyze the combined effects of high blood sugar and beta-amyloid protein in living animals.
The group of scientists, led by Scintillon faculty members Stuart Lipton, MD, PhD, Rajesh Ambasudhan, PhD, and Tomohiro Nakamura, PhD, found that both excess sugar and beta-amyloid protein caused a rise in nitric oxide and other free radical species. This change led to the modification of multiple enzymes through a chemical process called S-nitrosylation. Because this modification changes enzymatic activity, it caused abnormal increases in both insulin and beta-amyloid protein. Moreover, the changes in enzyme activity led to damage of synapses, the region where nerve cells communicate with one another in the brain. The combination of high sugar and beta-amyloid protein caused the greatest loss of synapses. Since loss of synapses correlates with cognitive decline in Alzheimer’s, high sugar and beta-amyloid coordinately contribute to memory loss.
“This work points to a new common pathway to attack both Type 2 diabetes, along with its harbinger, metabolic syndrome, and Alzheimer’s disease,” stated Dr. Lipton, study leader and Distinguished Professor at Scintillon and a clinical neurologist at UC San Diego. “It also means that we now know these diseases are related on a molecular basis, and hence, they can be treated with new drugs on a common basis,” stated Dr. Ambasudhan, a senior author and Assistant Professor at the Scintillon Neurodegenerative Disease Center.
About 40% of the US population suffers from metabolic syndrome, which is characterized by obesity, increased blood pressure, and abnormal handling of sugar. Hence, this population may not only be at risk for developing diabetes, as previously thought, but also for developing the symptoms of Alzheimer’s disease, currently known to affect about 5.3 million Americans.
Scientists not involved in the research agree that the new findings have important ramifications for the future treatment of these seemingly diverse diseases now that their molecular relationship is being elucidated.
Dr. Mohd Waseem Akhtar, a postdoctoral fellow in Lipton laboratory, is the lead author of the study. Additional team members include Scott McKercher, Sara Sanz-Blasco, Walid Soussou, Kevin Chon, Michelle Lee, Nima Dolatabadi and James Parker.
Nature Communications DOI: 10.1038/ncomms10242
Elevated glucose and oligomeric β-amyloid disrupt synapses via a common pathway of aberrant protein S-nitrosylation.
The Scintillon Institute is a non-profit research institute located at the heart of the San Diego biotechnological community. The institute is committed to developing new technologies to improve the human condition, is largely supported by NIH grants and philanthropy, and is dedicated to eradicating neurodegenerative diseases.