Impact of IL-21-associated peripheral and brain crosstalk on the Alzheimer’s disease neuropathology

Abstract

Alzheimer’s disease (AD) is associated with dysregulated immune and inflammatory responses. Emerging evidence indicates that peripheral immune activation is linked to neuroinflammation and AD pathogenesis. The present study focuses on determining the role of IL-21 in the pathogenesis of AD using human samples and the 5xFAD mice model. We find that the levels of IL-21 are increased in the periphery of both humans and mice in AD. In addition, the proportions of IL-21 target cells, Tfh and B plasma cells as well as activation of monocytes is increased in PBMCs from AD and mild cognitively impaired (MCI) subjects as compared to age-matched controls, indicating immune activation. In contrast, the percentage of B1 cells that control inflammation is decreased. These changes are due to IL-21 as the expression of IL-21 receptor (IL-21R) is higher on all these cells in AD. Furthermore, treatment with recombinant IL-21 in AD mice also leads to similar alterations in Tfh, B, B1, and macrophages. The effect of IL-21 is not confined to the periphery since increased expression of IL-21R is also observed in both humans and mice hippocampus derived from the AD brains. In addition, mice injected with IL-21 display increased deposition of amyloid beta (Aβ) plaques in the brain which is reduced following anti-IL-21R antibody that blocks the IL-21 signaling. Moreover, activation of microglia was enhanced in IL-21-injected mice. In keeping with enhanced microglial activation, we also observed increased production of pro-inflammatory cytokines, IL-18 and IL-6 in IL-21-injected mice. The microglial activation and cytokines were both inhibited following IL-21R blockage. Altogether, IL-21 escalates AD pathology by enhancing peripheral and brain immune and inflammatory responses leading to increased Aβ plaque deposition. Graphical abstract IL-21 impacts AD neuropathology by enhancing peripheral and neuronal immune activation, inflammation, and Aβ plaque deposition. Increased levels of IL-21 in the circulation of AD and MCI subjects enhances the proportions of Tfh and B plasma cells indicative of peripheral immune activation. On the other hand, the proportions of B1 cells that help reduce inflammation and clear Aβ are reduced. In addition to the periphery, IL-21 also acts on the brain via IL-21 receptor, IL-21R that displays increased expression in the hippocampi of AD and MCI subjects. IL-21 enhances the activation of microglia, induces the secretion of pro-inflammatory cytokines and deposition of Aβ plaques in the brain in AD.

Exome-wide analysis reveals role of LRP1 and additional novel loci in cognition

“…rs12932325 is an eQTL for IL21R ( Table S29 ) that impacts Alzheimer disease pathology by enhancing brain and peripheral immune and inflammatory responses and leads to increased deposition of Aβ plaques. 51 Both the models controlling for LDL and total cholesterol levels independently yield an intronic variant in PTPN11 as a significant hit for complex processing speed. The lead eQTL variant near ±500 kb of this variant significantly controls expression of PTPN11 in the substantia nigra of the brain ( Table S30 ).…”

Peripheral immune markers and amyotrophic lateral sclerosis: a Mendelian randomization study

“…Under the reflection of CD8 + T cells to chronic antigen presentation, IL-21 may be involved in driving autoimmune diseases (Ren et al, 2021). IL-21 is elevated in the serum of AD and MCI patients, and blocking IL-21 can alleviate neuroinflammation and Aβ plaques in 5 × FAD mice (Agrawal et al, 2022). Although a meta-analysis showed that Mendelian randomization analysis of the causal association between immune markers and amyotrophic lateral sclerosis.…”

Exome-wide analysis reveals role ofLRP1and additional novel loci in cognition

“…rs12932325 is an eQTL for IL21R (Supplementary Table 11) which impacts Alzheimer's disease pathology by enhancing brain and peripheral immune and inflammatory responses and leads to increased deposition of Aβ plaques. 56 Both the models controlling for LDL and total cholesterol levels independently yield a novel intronic variant in PTPN11 as a novel significant hit for complex processing speed. The lead eQTL variant near ±500 kb of this variant significantly controls expression of PTPN11 in the substantia niagra of the brain (Supplementary Table 12).…”