Scientists revealed a molecular link between the pathogenesis of type 2 diabetes and Alzheimer’s disease, shedding light on an association long thought to exist between the two diseases but poorly understood. In the study, they demonstrated that an excess of blood sugar (diabetes) and beta-amyloid protein (Alzheimer’s) induce the same effect on several enzymes in the brain.
The study, titled “Elevated glucose and oligomeric β-amyloid disrupt synapses via a common pathway of aberrant protein S-nitrosylation,” was published in Nature Communications.
Several epidemiological studies have shown a correlation between the risk of developing metabolic syndrome (MetS) and type 2 diabetes, and the onset of Alzheimer’s disease (AD). Studies in mouse models of prediabetes, metabolic syndrome or type 2 diabetes have also shown that these in vivo models develop behavioral, synaptic, and molecular deficits that are characteristic of AD. Despite these observations largely suggesting that MetS/type 2 diabetes increases the risk for AD, the molecular mechanisms that link these metabolic and cognitive diseases were not well known.
Scientists with the Neurodegenerative Disease Center at San Diego’s Scintillon Institute for Biomedical and Bioenergy Research, led by Dr. Stuart Lipton, Dr. Rajesh Ambasudhan, and Dr. Tomohiro Nakamura, genetically programmed human skin cells to pluripotent stem cells, which were then used to derive nerve cells, in an approach often called a “disease-in-a-dish.” The team also used mouse models of each disease to investigate common molecular pathways, and observe the effects of high blood sugar and beta-amyloid protein in living animals.
The study showed that both diseases are oxidizing, and alter the redox state of neurons in the cortical and hippocampal regions of the brain. Both excess of sugar and beta-amyloid protein — amyloid plaques composed of beta-amyloid protein aggregates are typically found in Alzheimer’s patients — caused a rise in nitric oxide and other oxygen free radicals/reactive oxygen species (ROS). The combined effect of sugar and the protein is more accentuated than either alone in terms of harmful production of neuronal reactive nitrogen species (RNS).
The oxidative changes observed led to the modification of multiple enzymes, through a process called S-nitrosylation. Such changes led to additional increases in beta-amyloid protein and glucose levels, which in turn caused mitochondrial and synaptic damage.
The study’s leader, Dr. Lipton, said in a press release, “This work points to a new common pathway to attack both Type 2 diabetes, along with its harbinger, metabolic syndrome, and Alzheimer’s disease.”
“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, its senior author.
