In a mouse model of brain pathology mediated by a subset of anti-DNA antibodies found in patients with systemic lupus erythematosus (SLE), ACE inhibition can preserve cognitive function, according to a new study. “The most important aspect of the study is that the results showed that damaged neurons can recover and cognition can be improved if microglial activation is controlled,” reports Betty Diamond, corresponding author of the study.

Her group has previously demonstrated that this subset of anti-DNA antibodies, which they term DNRAbs, cross-react with the N-methyl-d-aspartate receptor (NMDAR). “We have been studying how and when these antibodies can contribute to the neuropsychiatric symptoms of SLE,” says Diamond. They developed a two-stage mouse model of neuropsychiatric lupus, in which DNRAbs are first induced by immunizing with a DWEYS peptide and the blood-brain barrier (BBB) is then disrupted using LPS treatment, resulting in acute excitotoxic neuron loss followed by long-term alterations in neuronal integrity and by spatial memory impairment.

Credit: Oleksiy Maksymenko Photography/Alamy Stock Photo

In this study, Diamond and colleagues sought to understand the mechanisms underlying the long-term cognitive impairment in this model. “We demonstrate that the antibody-mediated neuronal death leads to microglial cell activation, and that microglial suppression can improve neuronal integrity and cognitive problems,” explains Diamond.

Using C1q-deficient mice, they showed that the decrease in dendritic complexity and spine density, but not the acute neuronal death, was dependent on C1q. Unlike wild-type DNRAb+ mice, C1q-deficient DNRAb+ mice behaved normally in an object-place memory task that tests spatial memory.

ACE inhibitors, commonly used to lower blood pressure, have previously been shown to suppress microglial activation. In the new study, treatment with a BBB-permeable ACE inhibitor, but not with a BBB-impermeable ACE inhibitor or saline, suppressed microglial activation and preserved dendritic integrity and cognitive function in the DNRAb+ mice.

Treatment with a BBB-permeable ACE inhibitor… suppressed microglial activation and preserved dendritic integrity and cognitive function in the DNRAb+ mice

“We plan to study the mechanisms for microglial activation, which might lead to therapeutic targets” says Diamond. “We also think clinical trials of ACE inhibitors in neuropsychiatric SLE are now warranted.”