Background/Purpose:

Cognitive dysfunction affects up to 90% of patients with systemic lupus erythematosus (SLE), however it is grossly under-recognized, the pathogenesis is poorly understood and no treatments are available. The anti-NMDAR antibody, a subset of anti-DNA antibodies termed DNRAbs, has been strongly associated with cognitive impairment, notably spatial memory impairment, in both mouse models and humans. In a mouse model, DNRAb-mediated brain pathology proceeds through two stages: excitotoxic neuron loss, followed by persistent neuroinflammation resulting in alteration in neuronal integrity and spatial memory impairment. Microglia-mediated inflammation is generally becoming well accepted as one of the main mediators of neurodegeneration. In our studies we are investigating the mechanisms of long-term neuronal dysfunction mediated by transient exposure to DNRAb. Also, with the emerging yet unknown role of the renin-angiotensin-system, notably angiotensin II, in microglia-mediated neuroinflammation in neurodegenerative diseases, angiotensin-converting enzyme (ACE) inhibition could be an attractive treatment option to test for preserving cognitive impairment through its effects on C1q and C1q’s inhibitory receptor, LAIR1.

Methods:

Mice immunized with DNRAb and then treated with LPS to breach the blood brain barrier and allow transient access of antibody to the hippocampus, were studied for loss of neuronal dendritic complexity using Golgi and for microglial activation with immunohistochemistry. Spatial memory was assessed with a battery of behavioral tests and CA1 hippocampal neuronal activity was assessed with electrophysiology studies. Microglia were depleted with Colony Stimulating Factor 1 Receptor (CSF1R) inhibitor PLX5622. Mice received centrally acting ACE inhibitor, captopril (or control peripherally acting ACE inhibitor, enalapril), one week after LPS for two weeks. ACE levels in brain tissue was checked before and after treatment. C1q-KO mice and LAIR1-Lyz2-Cre mice were also studied to assess the roles of C1q and LAIR-1 in glia-mediated neuroinflammation.

Results:

DNRAb mice had significantly decreased dendritic complexity (p<0.01), and impaired spatial memory (p<0.01), which was preserved in CSF1R-inhibitor treated mice (p<0.03) and in C1q-KO mice. These findings suggest that activated microglia and C1q are critical mediators of DNRAb-associated neuronal damage and spatial memory impairment. We further showed that centrally acting ACE inhibitors can preserve neuronal dendrite complexity (p<0.03) and cognitive performance (p<0.01) in the mouse model. The effect of captopril was diminished in the LAIR1-Lyz2Cre knockout (p<0.0001), signifying that LAIR1 is important in the protective mechanism of captopril.

Conclusion:

ACE inhibition may be considered as a safe and promising class of therapeutics in cognitive impairment in SLE and represents a strong candidate for future clinical trials aimed at mitigating cognitive dysfunction. Further studies to understand the mechanism of action of ACE inhibitors are needed.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/angiotensin-converting-enzyme-inhibitors-prevent-spatial-memory-impairment-in-a-mouse-model-of-neuropsychiatric-lupus-through-lair1-mediated-inhibition-of-microglial-activation/