Alzheimer’s disease, characterized by brain deposits of amyloid-β plaques and neurofibrillary tangles, is also linked to neurovascular dysfunction and blood–brain barrier breakdown, affecting the passage of substances into and out of the brain. We hypothesized that treatment of neurovascular alterations could be beneficial in Alzheimer’s disease. Annexin A1 (ANXA1) is a mediator of glucocorticoid anti-inflammatory action that can suppress microglial activation and reduce blood–brain barrier leakage. We have reported recently that treatment with recombinant human ANXA1 (hrANXA1) reduced amyloid-β levels by increased degradation in neuroblastoma cells and phagocytosis by microglia. Here, we show the beneficial effects of hrANXA1 in vivo by restoring efficient blood–brain barrier function and decreasing amyloid-β and tau pathology in 5xFAD mice and Tau-P301L mice. We demonstrate that young 5xFAD mice already suffer cerebrovascular damage, while acute pre-administration of hrANXA1 rescued the vascular defects. Interestingly, the ameliorated blood–brain barrier permeability in young 5xFAD mice by hrANXA1 correlated with reduced brain amyloid-β load, due to increased clearance and degradation of amyloid-β by insulin degrading enzyme (IDE). The systemic anti-inflammatory properties of hrANXA1 were also observed in 5xFAD mice, increasing IL-10 and reducing TNF-α expression. Additionally, the prolonged treatment with hrANXA1 reduced the memory deficits and increased synaptic density in young 5xFAD mice. Similarly, in Tau-P301L mice, acute hrANXA1 administration restored vascular architecture integrity, affecting the distribution of tight junctions, and reduced tau phosphorylation. The combined data support the hypothesis that blood–brain barrier breakdown early in Alzheimer’s disease can be restored by hrANXA1 as a potential therapeutic approach.

The CCAAT/Enhancer Binding Protein β (C/EBPβ) transcription factor is activated by multiple inflammatory stimuli, including IL-17 and LPS, and C/EBPβ itself regulates numerous genes involved in inflammation. However, the role of C/EBPβ in driving autoimmunity is not well understood. Here, we demonstrate that Cebpb−/− mice are resistant to EAE. Cebpb−/− mice exhibited reduced lymphocyte and APC infiltration into CNS following EAE induction. Furthermore, MOG-induced Th17 cytokine production was impaired in draining LN, indicating defects in Th17 cell priming. In vitro Th17 polarization studies indicated that T cell responses are not inherently defective, instead supporting the known roles for C/EBPβ in myeloid lineage cell activation as the likely mechanism for defective Th17 priming in vivo. However, we did uncover an unexpected role for C/EBPβ in regulating ll23r expression in APCs. ChIP assays confirmed that C/EBPβ binds directly to the Il23r gene promoter in dendritic cells and Th17 cells. These data establish C/EBPβ as a key driver of autoimmune inflammation in EAE, and propose a novel role for C/EBPβ in regulation of IL-23R expression.

b-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is best known for its role in Alzheimer's disease amyloid plaque formation but also contributes to neurodegenerative processes triggered by CNS injury. In this article, we report that BACE1 is expressed in murine CD4 + T cells and regulates signaling through the TCR. BACE1-deficient T cells have reduced IL-17A expression under Th17 conditions and reduced CD73 expression in Th17 and inducible T regulatory cells. However, induction of the Th17 and T regulatory transcription factors RORgt and Foxp3 was unaffected. BACE1-deficient T cells showed impaired pathogenic function in experimental autoimmune encephalomyelitis. These data identify BACE1 as a novel regulator of T cell signaling pathways that impact autoimmune inflammatory T cell function.

A c c e p t e d M a n u s c r i p t >Oral cis-2-pentenenitrile causes loss of vestibular function in rats >Loss of hair cells in the vestibular sensory epithelia causes the functional deficit >CYP blocker 1-aminobenzotriazole blocks the vestibular effect of cis-2-pentenenitrile >Oral cis-2-pentenenitrile does not cause significant neuronal degeneration system apart from neurite labeling in the olfactory glomeruli. We conclude that cis-2-pentenenitrile causes vestibular toxicity in a similar way to allylnitrile, cis-crotononitrile and 3,3'-iminodipropionitrile (IDPN), and also shares other targets such as the olfactory system with these other nitriles. The present data also suggest that CYPmediated bioactivation is involved in cis-2-pentenenitrile toxicity.