ACE Inhibitors May Protect Nerve Cells from Damage That Harms Cognition, Early Lupus Study Reports

Immune cells of the brain and spinal cord, called microglia, contribute to the cognitive deficits seen in some systemic lupus erythematosus (SLE) patients by trimming neurons in the central nervous system, researchers at The Feinstein Institute for Medical Research suggest.

Medications commonly used to treat high blood pressure – called ACE inhibitors – were able to to reduce the activity of these cells, protecting mice from neuronal damage. These inhibitors might help to protect SLE patients from such damage, the researchers believe.

Their study, “Lupus antibodies induce behavioral changes mediated by microglia and blocked by ACE inhibitors,” was published in the Journal of Experimental Medicine.

SLE is an autoimmune, inflammatory disease characterized by the production of antibodies that attack patients’ healthy cells, particularly their nuclear proteins and DNA. In 40 to 90 percent of patients, the disease affects the brain, causing cognitive impairments like confusion and memory loss.

Patients with widespread manifestations of lupus in the brain often show evidence of particular antibodies, called DNRAbs, that target both DNA and a key brain protein called NMDAR.

The findings led researchers to hypothesize that DNRAbs might be causing brain injury by binding to NMDAR in neurons (nerve cells) in the brain. Antibodies don’t usually cross the blood-brain barrier, but if a patient is exposed to an external stimuli, like a brain injury or infection, a breach in this protective barrier may open.

Prior studies in mice demonstrated that as soon as the antibodies enter the brain, the animals experience neuronal cell death or a loss of the connections between neurons — called synapses — leading to memory loss. But the mechanisms behind these events are not well understood.

Researchers investigated the role of microglia — the immune cells that populate the brain and spinal cord — in this process. Microglia patrol the brain for threats and are responsible for clearing the debris of death and dying neurons. Importantly, these immune cells can also trim excess neuronal synapses.

Investigators induced DNRAb production in mice, and added a stimulus that allowed them temporary access to the brain. Then, mice were divided into three groups: groups one and two received a drug that depletes microglia, and group three received no treatment. Only the medication given to group one, however, could enter the brain.

Mice in group one had fewer microglia in the brain than those in other groups, and had a similar neuronal complexity as mice without DNRAb antibodies.

“The fact that a reduction in microglia number is associated with maintenance of neuronal integrity strongly suggests that microglia are required for the structural alterations in neurons in the DNRAb-mediated model of cognitive impairment,” the researchers wrote. They found that microglia were activated when DNRAbs entered the brain.

Researchers also showed that the mechanisms of neuronal trimming were related to a protein of the complement system — a pathway important in lupus development — called C1q. In fact, mice without this protein were not sensitive to DNRAb-mediated loss of neuronal connections.

ACE inhibitors are a class of drugs used to treat high blood pressure, but studies in Alzheimer’s disease suggest that they also decrease microglia activation and reduce neuronal damage. For this reason, researchers investigated if blocking ACE benefited mice with DNRAb-induced cognitive impairment.

Treatment with the ACE inhibitor captopril indeed reduced microglial activation and preserved neuronal synapses. This was linked to a preservation of cognitive function.

The results “suggest suggest that ACE inhibitors may be considered a promising class of therapeutics in cognitive impairment in SLE,” researchers said, while adding that further studies are required to understand the mechanisms by which ACE inhibitors act on microglia cells.

And, they added, as treatments already in wide use, ACE inhibitors “protective in this model, can easily move to clinical trial as a potential treatment for [lupus] patients.”