Researchers at the Scintillon Institute for Biomedical and Bioenergy Research, San Diego, have discovered that the high blood sugar levels that mark type 2 diabetes and the plaque-forming β-amyloid protein found in Alzheimer’s disease (AD) cause the same alterations in several brain enzymes.
The findings explain the association long observed between AD and diabetes. The results, published in the online edition of Nature Communications, are from the study titled “Elevated glucose and oligomeric β-amyloid disrupt synapses via a common pathway of aberrant protein S-nitrosylation.”
The team at Scintillon, led by Stuart Lipton, Rajesh Ambasudhan, and Tomohiro Nakamura, used a number of approaches to study the presumed connection. The disease-in-a-dish model allowed them to study molecular pathways active in both AD and diabetes. Specifically, the team used induced pluripotent stem cells, derived from patients, to grow human neurons, and also mouse models of both diseases.
Both high blood sugar and β-amyloid increased levels of nitric oxide and other free radical species, starting a chain of events leading to further deterioration. The free radical species induced S-nitrosylation of multiple enzymes, a process that increases enzyme activity. This, in turn, resulted in a decreased degradation, and hence accumulation, of both β-amyloid and insulin.
The enzymatic changes also damaged neuronal connections (synapses) in the brain. While both excess sugar and β-amyloid could induce synaptic damage, the combination of the two induced the greatest loss of neuronal connections. These findings clearly show that increased sugar levels contribute to memory loss in AD.
The findings also introduce a new risk for people with metabolic syndrome and known to be at risk for diabetes — the possible development of AD.
“This work points to a new common pathway to attack both Type 2 diabetes, along with its harbinger, metabolic syndrome, and Alzheimer’s disease,” Dr. Lipton, study leader, distinguished professor at Scintillon and a clinical neurologist at UC San Diego, said in a press release.
“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,” added Dr. Ambasudhan, a senior author and assistant professor at Scintillon.
According to the press release, scientists not involved in the research agreed that the findings, by helping to explain the molecular link between AD and diabetes, could have far-reaching consequences for the future treatment of two seemingly diverse diseases.