Macroautophagy is a crucial cellular process in the central nervous system. Its deregulation is implicated in many brain degenerative (Alzheimer’s disease, Parkinson’s disease)1,2 and auto-immune pathologies (amyotrophic lateral sclerosis, multiple sclerosis)3,4. Changes in this intracellular pathway of self-degradation has also been associated with the pathogenesis of systemic lupus erythematosus5,6. We describe here, for the first time, a deregulation of macroautophagy in the central nervous system in MRL/lpr mice, a lupus-prone murine model. Namely, MRL/lpr mice display behavioral deficits in the T-maze7 indicating compromised hippocampal functioning8. By magnetic resonance imaging, we observed structural changes in MRL/lpr brain9 and interestingly, we found a correlation between brain mass loss and deficient alternation behavior. More precisely, we identified neuronal and astrocytic abnormalities throughout the hippocampus [i.e. dentate gyrus, cornu ammonis 3 (CA3)]. Same regions displayed a higher number of autophagosomes indicating either deficiency of the process of fusion of autophagosomes with lysosomes and/or an increased autophagic flux. Congruently, we identified increased levels of cleaved form of complement C3 protein in CA3 hippocampal layer. Lastly, using a glioblastoma cell line, we noticed that induction of macroautophagy by rapamycin produces higher levels of cleaved C3 and, inversely, the cysteine protease inhibitor E64d reduces C3 processing into its active forms. In conclusion, we propose a model where deregulation of autophagy might lead to production of proinflammatory and damaging molecules in the hippocampus resulting in noticeable neurodegeneration. Future experiments will address the question of translatability of these mechanistic data to MRL/lpr mouse model and human disease.