Auto-Antibodies a New, Unsuspected Source of Cognitive Damage, but Drugs Could Prevent Decline
Sep 9, 2004
For years, experts have puzzled over the fact that lupus patients often experience accelerated declines in thinking and memory as they age, despite the absence of the usual neurological culprits, such as neurovascular inflammation or stroke.
Now a husband-and-wife team of researchers, including Dr. Bruce T. Volpe, Professor of Neurology and Neuroscience at Weill Cornell Medical College in New York and Attending Neurologist at New-York Presbyterian Hospital and Burke Medical Research Institute in White Plains, say they have a new approach to this puzzle that may open the door to treatments that slow or prevent lupus-related cognitive decline.
An immune system antibody that lingers in especially high concentrations in lupus patients appears to attack and kill brain cells, Dr. Volpe's team reports in the journal Immunity.
"There may be an approach to attenuating the effect of the antibody, however," he said.
Systemic lupus erythematosus (SLE) is an autoimmune disorder that causes inflammation, pain, and tissue damage throughout the body. Often chronic, it affects mainly women. There is currently no cure for lupus, although treatments can ease symptoms.
As treatments lengthened the lives of lupus sufferers, doctors began to notice increased cognitive decline in many of their aging patients. However, the brain cell death found in these patients wasn't always linked to expected causes, such as stroke or inflammation.
Dr. Volpe said his work was spurred by a "brilliant" discovery a few years ago by his wife, Dr. Betty Diamond, of Albert Einstein College of Medicine, New York. Her team identified a specific autoimmune antibody, called anti-NR2, which also has a special affinity for glutamate receptors lying on the surface of neurons and other cells.
Healthy individuals usually rid themselves of most of these auto-antibodies, but Dr. Diamond found high blood concentrations of the antibodies in 40 to 60 percent of lupus patients.
In his team's most recent study, Dr. Volpe used a mouse model to determine just how these antibodies breach the blood-brain barrier, allowing them access to healthy neurons.
"The temporary inflammation you can get during a cold, the flu, or lupus flare-up can 'open the gate' for antibodies to cross the blood-brain barrier," he explained, so the mice received an inflammation-inducing compound to mimic that process.
Seven days after this inflammation occurred, the brains of mice that were immunized to produce high concentrations of anti-NR2 "had already lost significant numbers of neurons, especially in the hippocampus, but also elsewhere throughout the cortex," Dr. Volpe said. Behavioral tests, performed by Dr. Patricio Huerta of New York University, suggested the mice still functioned well in terms of motor skills, but had suffered memory declines.
So, now that the researchers knew lupus-linked auto-antibodies were attacking and killing brain cells, could they find a way to stop it?
In another experiment, the multi-institutional team from Weill Cornell and Einstein injected antibody-laden mice with memantine, a drug that competes with the antibody for a parking space on each neuron's glutamate receptor.
The treatment stopped the antibody binding.
"When the memantine was injected, we stopped the neuron's stress response, and we think it might have effectively preserved the neuron by interrupting the auto-antibody's access to the receptor," Dr. Volpe said.
"More tests are required before we approach treating humans, but this approach could lead to new ways of slowing or stopping the cognitive decline seen in many older lupus patients."
The study has even broader implications, casting the immune system as a key player in yet other disease processes, this time targeted neurological damage. "The idea is that these antibodies may affect cognition — they certainly do in mice," Dr. Volpe said.
The next step, he said, is to use MRI technology to determine the exact permeability of the blood-brain barrier when it comes to anti-NR2 antibodies. Further experiments will also look closer at "just how the antibody binds and kills," he said, and what might be done to prevent that.
The study received funding from the National Institutes of Health, the Lupus Research Institute, the Burke Medical Research Institute, and the Pew Latin American Fellows Program in the Biomedical Sciences.
Co-researchers on the study included Lorraine A. DeGiorgio, of Burke Medical Research Institute and Weill Cornell Medical College, New York; Dr. Betty Diamond, Dr. Hoby Patrick Hetherington, Czeslawa Kowal, and Tsukasa Nakaoka, of Albert Einstein College of Medicine, New York; and Dr. Patricio T. Huerta, of the Center for Neural Science, New York University.