Short-term deficits and CA3 hippocampal damage in a murine model of lupus

Background: In some autoimmune diseases, the central nervous system can be affected as a result of systemic inflammation. Along with inducing aberrant brain-resident immune cell activation, systemic inflammation may lead to a leakage of the blood–brain barrier, and production of antibodies cross-reacting with brain antigens. This is exemplified in systemic lupus erythematosus (SLE) whose neuropsychiatric form (NPSLE) is extensively studied in the lupus-prone murine model MRL/lpr mice. The aim of our study was to characterize the behavioral outcomes of MRL/lpr mice, to link them to cerebral and autoimmune abnormalities, and to evaluate the effects of the therapeutic phosphopeptide P140 developed in our team. Method: Y- and T-maze alternation were used to assess short-term memory in MRL/lpr and MRL+/+ mice treated or not with P140. Brains were collected and used for flow cytometry to evaluate cellular infiltration and histology to visualize integrity. Results: Compared to MRL+/+ littermates, MRL/lpr mice display higher proteinuria (P≤0.05) whose development is slowed down by P140 treatment (P≤0.05), reduced brain weight (P≤0.01), and cerebral infiltrates by immune cells (P≤0.001). They are significantly impaired in the Y-maze and the T-maze (P≤0.05 and P≤0.01, respectively). The latter deficit is totally compensated by P140 administration (P≤0.001). Congruently, Nissl staining showed neuronal loss in the CA3 hippocampal region of diseased MRL/lpr mice. Conclusion: In addition to confirming that MRL/lpr mice are affected at the periphery, as evidenced by higher proteinuria levels, and centrally, as attested by reduced brain weight, our present data highlight that MRL/lpr mice suffer from short-term memory defect, likely reflecting hippocampal damage, and which may be mediated by infiltration of peripheral immune cells. Furthermore, the peptide P140 is a promising drug as it compensates such short-term memory deficit. We suggest that SLE specially impacts memory due to peripheral activation, an issue that should be addressed when diagnosing and treating cognitively-impaired SLE patients. Collectively, these data demonstrate that P140 exerts beneficial cognitive effect and arouse hope for patients suffering from NPSLE for whom there is nowadays no specific treatment.