A research team led by Dennis Selkoe, MD, Center for Neurologic Diseases, BWH Department of Neurology, has uncovered the dynamics of how molecules, known as a-beta oligomers, contribute to nerve-to-nerve communication breakdown in Alzheimer’s disease (AD).
They found that neurotoxic a-beta oligomers (a string of a-beta molecules) were transferred from the brain’s interstitial fluid onto adjacent brain membranes faster than nontoxic a-beta monomers (normal, single molecules), and were observed to bind strongly to GM1 ganglioside molecules found on the surface of adjacent brain membranes. In mouse hippocampal slices, the researchers observed that blocking the sialic acid residue on GM1 prevented the loss of long-term synaptic signaling between nerve cells that is usually caused by the oligomers.
The researchers also observed substantial levels of a GM1-bound form of a-beta 42 recovered from the brain membrane fractions in the mice. They then also detected this GM1-bound a-beta 42 in human cerebral spinal fluid, suggesting it as a potential future biomarker of a-beta-related membrane dysfunction.
“Our findings demonstrate a mechanism whereby hydrophobic a-beta oligomers, which are key toxins harming synapses in the AD brain, become sequestered onto GM1 ganglioside on cell membranes and may there induce progressive functional and structural changes in the brain,” said Selkoe. “We are now trying to develop a sensitive immunoassay to quantify this special form of a-beta protein [GM1-a-beta 42] in human brain and cerebral spinal fluid.”
The study was published April 16, 2014 in Neuron.