Altered Affect and Increased CLIP+ B cells in the Meningeal Lymphatics of 5xFAD mice are mitigated by antagonizing MHCII‐associated invariant chain (CLIP)

Abstract

AbstractBackgroundDepression often occurs prior to Alzheimer’s disease (AD) and both depression and AD have been linked to immune mechanisms. A key role for activated B cells in AD pathogenesis was recently identified. The study found that B cell depletion reduced Aβ plaque accumulation, neuroinflammation, and behavioral deficits in three AD transgenic mouse models. Our work has shown that treatment with a peptide antagonist for Major histocompatibility complex class II (MHCII) invariant peptide (CLIP), a key component in the transition between innate and adaptive immunity, results in selective depletion of pro‐inflammatory, CLIP+ve B cells and neuroprotection. We hypothesized that selective depletion of CLIP+ve B cells in the 5xFAD model of AD would reduce depression‐associated behavioral deficits.Method11‐week‐old male WT and 5xFAD mice underwent social interaction and burrowing pre‐testing. 12‐week‐old mice were treated once with a competitive antagonist peptide (CAP) or vehicle, followed by social interaction and burrowing testing once a month for 5 months. 6 months post‐treatment, meningeal lymphatics were collected, stained, and analyzed flow cytometrically for markers of B cells (CD19), T cells (CD3), and CLIP.ResultAffective alterations were observed in 5xFAD mice as early as 11 weeks of age and persisted up to 9 months of age. CAP treatment in 5xFAD mice protected against an age‐associated decline in social interaction. At 9 months of age 5xFAD mice were found to have significantly more B cells and CLIP+ve B cells in the meningeal lymphatics when compared to age‐matched WT, and CLIP+ve B cells were significantly decreased by a single CAP injection at 3 months of age.ConclusionA key function of B cells is their role as antigen presenting cells (APCs). CLIP occupies the MHCII antigen binding groove until it is displaced by antigen to be presented to CD4+ T cells, marking the transition between an innate and an adaptive immune response. Our findings suggest that 5xFAD mice exhibit depression‐associated behavior by 11 weeks of age, that CLIP+ve cells are elevated in 5xFAD mice, and that antagonizing CLIP depletes these B cells and functionally protects mice genetically predisposed to AD.