Activation of brain cells called microglia likely contributes to the memory loss and other cognitive impairments suffered by many patients with systemic lupus erythematosus, according to new research from The Feinstein Institute for Medical Research. The study shows that ACE inhibitors - a class of drugs commonly used to treat hypertension - can block this process in mice and might therefore be used to preserve the memory of lupus patients.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease that arises when the body starts to make antibodies that target its own, healthy cells, often specifically recognizing DNA. Patients can suffer a wide variety of symptoms, but as many as 90% develop neuropsychiatric lupus, which is often characterized by cognitive impairments such as memory loss or confusion.

Betty Diamond and colleagues at The Feinstein Institute for Medical Research in Manhasset, NY, previously found that lupus patients experiencing memory loss often produce antibodies - called DNRAbs - that recognize both DNA and a critical brain protein called the NMDA receptor, NMDAR.

Antibodies are usually unable to enter the brain, but, after injury or infection, DNRAbs are thought to gain temporary access to the brain, where they can target neurons expressing NMDAR. This causes the neurons to die or lose the synapses that connect them to neighboring nerve cells, resulting in memory loss or other cognitive defects.

Microglia In SLE

Diamond and colleagues suspected that microglia might be responsible for trimming the connections between neurons after exposure to DNRAbs. These cells help clear away the debris of dead and dying neurons and can also remove excessive or unwanted synapses during brain development.

[caption id="attachment_97265” align="aligncenter” width="680”]Microglia are critical to dendritic pruning in NPSLE. Microglia are critical to dendritic pruning in NPSLE.
(A) Top, schematic representation of the hippocampus, with the transverse section showing the CA1 ROI (yellow square) to study microglia depletion. Bottom, immunized mice were treated with CSF1R inhibitors PLX5622 (BBB permeable) or PLX73086 (BBB impermeable) for 5 wk, after which their brains were analyzed for morphological changes.
(B) Representative sections of the CA1 region with DAB staining for Iba1 allows visualization of microglia in untreated mice (standard chow), as well as PLX5622- and PLX73086-treated mice. Bar, 50 µm.
(C) Decreased number of microglia in PLX5622-treated mice (n = 3) compared with PLX73086-treated mice (n = 3) and standard chow-treated mice (**, P < 0.005; ***, P < 0.001; n = 3; n = 12 sections per group; Mann-Whitney test).
(D) Tracings of CA1 neurons in the DNRAb+ and DNRAb− groups after PLX5622 and PLX73086 treatments.
(E) Analysis of dendritic complexity shows no difference between PLX5622-treated groups (DNRAb− = 21 neurons; DNRAb+ = 20 neurons; ns, not significant, Kolmogorov-Smirnov test).
(F) Treatment with PLX73086 reveals significant decrease in dendritic complexity in DNRAb+ mice compared with DNRAb− mice (DNRAb− = 21 neurons, DNRAb+ = 23 neurons; **, P < 0.005; Kolmogorov-Smirnov test).
Credit: Jacquelyn Nestor, et al CC-BY[/caption]

To address the role of microglia in SLE, Diamond and colleagues analyzed mice that produce DNRAbs capable of penetrating the brain and inducing memory loss. The researchers found that microglia are activated when DNRAbs enter the brain and that a protein called C1q attracts microglia to the synapses of neurons targeted by these antibodies.

Deleting the C1q protein, or depleting the microglial cells themselves, prevented neurons from losing their synapses after exposure to DNRAbs.

ACE Inhibitors

ACE inhibitors such as captopril are a class of drugs used to treat high blood pressure. They are also known to block the activation of microglia. Diamond and colleagues found that captopril treatment protected neurons from DNRAbs and preserved the memory of mice producing these antibodies.

“Our study suggests that ACE inhibitors are a promising class of therapeutics that can easily move into clinical trials aimed at mitigating the cognitive dysfunction associated with neuropsychiatric lupus,“

Diamond says.

An angiotensin-converting-enzyme inhibitor (ACE inhibitor) is a pharmaceutical drug used primarily for the treatment of elevated blood pressure and congestive heart failure. This group of drugs causes relaxation of blood vessels as well as a decrease in blood volume, which leads to lower blood pressure and decreased oxygen demand from the heart. They inhibit the angiotensin-converting enzyme, an important component of the renin–angiotensin system.

Frequently prescribed ACE inhibitors include benazepril, zofenopril, perindopril, trandolapril, captopril, enalapril, lisinopril, and ramipril.

The study demonstrates that ACE inhibition is linked with less active microglia, and with preservation of neuronal structure of structure and function, implicating microglia in neuronal pathology. The exact mechanism of how ACE inhibition prevents or reverses microglial activation needs further study.

The study was supported by grants from the National Institutes of Health

Jacquelyn Nestor, Yoshiyuki Arinuma, Tomás S. Huerta, Czeslawa Kowal, Elham Nasiri, Nina Kello, Yuichiro Fujieda, Alison Bialas, Tim Hammond, Uma Sriram, Beth Stevens, Patricio T. Huerta, Bruce T. Volpe, Betty Diamond Lupus antibodies induce behavioral changes mediated by microglia and blocked by ACE inhibitors Journal of Experimental Medicine Sep 2018, jem.20180776; DOI: 10.1084/jem.20180776

Top Image: Neurons were cultured alone and stained for GluN1 (green), labeled HMGB1 (red), MAP2 (cyan), and DAPI (blue). C_redit: Jacquelyn Nestor, et al CC-BY_

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